Reduction of heart rate variability by parasympathetic stimulation

ABSTRACT

Apparatus is provided that includes an electrode device, adapted to be coupled to a vagus nerve of a subject, and a control unit, adapted to drive the electrode device to apply to the vagus nerve a current that reduces heart rate variability of the subject. Also provided is a method comprising applying to a vagus nerve of a subject a current that reduces heart rate variability of the subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present patent application is a continuation-in-part of PCT PatentApplication PCT/IL03/00431, filed May 23, 2003, entitled, “Selectivenerve fiber stimulation for treating heart conditions,” which:

(a) is a continuation-in-part of U.S. patent application Ser. No.10/205,475, filed Jul. 24, 2002, entitled, “Selective nerve fiberstimulation for treating heart conditions,” which is acontinuation-in-part of PCT Patent Application PCT/IL02/00068, filedJan. 23, 2002, entitled, “Treatment of disorders by unidirectional nervestimulation,” which is a continuation-in-part of U.S. patent applicationSer. No. 09/944,913, filed Aug. 31, 2001, entitled, “Treatment ofdisorders by unidirectional nerve stimulation,” now U.S. Pat. No.6,684,105 and

-   -   (b) claims the benefit of US Provisional Patent Application        60/383,157 to Ayal et al., filed May 23, 2002, entitled,        “Inverse recruitment for autonomic nerve systems.”

Each of the above-referenced applications is assigned to the assignee ofthe present patent application and incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to treating patients byapplication of electrical signals to a selected nerve or nerve bundle,and specifically to methods and apparatus for stimulating the vagusnerve for treating heart conditions.

BACKGROUND OF THE INVENTION

The use of nerve stimulation for treating and controlling a variety ofmedical, psychiatric, and neurological disorders has seen significantgrowth over the last several decades. In particular, stimulation of thevagus nerve (the tenth cranial nerve, and part of the parasympatheticnervous system) has been the subject of considerable research. The vagusnerve is composed of somatic and visceral afferents (inward conductingnerve fibers, which convey impulses toward the brain) and efferents(outward conducting nerve fibers, which convey impulses to an effectorto regulate activity such as muscle contraction or glandular secretion).

The rate of the heart is restrained in part by parasympatheticstimulation from the right and left vagus nerves. Low vagal nerveactivity is considered to be related to various arrhythmias, includingtachycardia, ventricular accelerated rhythm, and rapid atrialfibrillation. By artificially stimulating the vagus nerves, it ispossible to slow the heart, allowing the heart to more completely relaxand the ventricles to experience increased filling. With largerdiastolic volumes, the heart may beat more efficiently because it mayexpend less energy to overcome the myocardial viscosity and elasticforces of the heart with each beat.

Stimulation of the vagus nerve has been proposed as a method fortreating various heart conditions, including heart failure and atrialfibrillation. Heart failure is a cardiac condition characterized by adeficiency in the ability of the heart to pump blood throughout the bodyand/or to prevent blood from backing up in the lungs. Customarytreatment of heart failure includes medication and lifestyle changes. Itis often desirable to lower the heart rates of patients suffering fromfaster than normal heart rates. The effectiveness of beta blockers intreating heart disease is attributed in part to theirheart-rate-lowering effect.

Bilgutay et al., in “Vagal tuning: a new concept in the treatment ofsupraventricular arrhythmias, angina pectoris, and heart failure,” J.Thoracic Cardiovas. Surg. 56 (1):71-82, July, 1968, which isincorporated herein by reference, studied the use of apermanently-implanted device with electrodes to stimulate the rightvagus nerve for treatment of supraventricular arrhythmias, anginapectoris, and heart failure. Experiments were conducted to determineamplitudes, frequencies, wave shapes and pulse lengths of thestimulating current to achieve slowing of the heart rate. The authorsadditionally studied an external device, triggered by the R-wave of theelectrocardiogram (ECG) of the subject to provide stimulation only uponan achievement of a certain heart rate. They found that when a pulsatilecurrent with a frequency of ten pulses per second and 0.2 millisecondspulse duration was applied to the vagus nerve, the heart rate could bedecreased to half the resting rate while still preserving sinus rhythm.Low amplitude vagal stimulation was employed to control inducedtachycardias and ectopic beats. The authors further studied the use ofthe implanted device in conjunction with the administration of Isuprel,a sympathomimetic drug. They found that Isuprel retained its inotropiceffect of increasing contractility, while its chronotropic effect wascontrolled by the vagal stimulation: “An increased end diastolic volumebrought about by slowing of the heart rate by vagal tuning, coupled withincreased contractility of the heart induced by the inotropic effect ofIsuprel, appeared to increase the efficiency of cardiac performance” (p.79).

U.S. Pat. No. 6,473,644 to Terry, Jr. et al., which is incorporatedherein by reference, describes a method for treating patients sufferingfrom heart failure to increase cardiac output, by stimulating ormodulating the vagus nerve with a sequence of substantiallyequally-spaced pulses by an implanted neurostimulator. The frequency ofthe stimulating pulses is adjusted until the patient's heart ratereaches a target rate within a relatively stable target rate range belowthe low end of the patient's customary resting heart rate.

U.S. Patent Application Publication 2003/0040774 to Terry et al., whichis incorporated herein by reference, describes a device for treatingpatients suffering from congestive heart failure. The device includes animplantable neurostimulator for stimulating the patient's vagus nerve ator above the cardiac branch with an electrical pulse waveform at astimulating rate sufficient to maintain the patient's heart beat at arate well below the patient's normal resting heart rate, therebyallowing rest and recovery of the heart muscle, to increase in coronaryblood flow, and/or growth of coronary capillaries. A metabolic needsensor detects the patient's current physical state and concomitantlysupplies a control signal to the neurostimulator to vary the stimulatingrate. If the detection indicates a state of rest, the neurostimulatorrate reduces the patient's heart rate below the patient's normal restingrate. If the detection indicates physical exertion, the neurostimulatorrate increases the patient's heart rate above the normal resting rate.

U.S. Patent Publication 2003/0045909 to Gross et al., which is assignedto the assignee of the present patent application and is incorporatedherein by reference, describes apparatus for treating a heart conditionof a subject, including an electrode device, which is adapted to becoupled to a vagus nerve of the subject. A control unit is adapted todrive the electrode device to apply to the vagus nerve a stimulatingcurrent, which is capable of inducing action potentials in a therapeuticdirection in a first set and a second set of nerve fibers of the vagusnerve. The control unit is also adapted to drive the electrode device toapply to the vagus nerve an inhibiting current, which is capable ofinhibiting the induced action potentials traveling in the therapeuticdirection in the second set of nerve fibers, the nerve fibers in thesecond set having generally larger diameters than the nerve fibers inthe first set.

The effect of vagal stimulation on heart rate and other aspects of heartfunction, including the relationship between the timing of vagalstimulation within the cardiac cycle and the induced effect on heartrate, has been studied in animals. For example, Zhang Y et al., in“Optimal ventricular rate slowing during atrial fibrillation by feedbackAV nodal-selective vagal stimulation,” Am J Physiol Heart Circ Physiol282: H1102-H1110 (2002), describe the application of selective vagalstimulation by varying the nerve stimulation intensity, in order toachieve graded slowing of heart rate. This article is incorporatedherein by reference.

The following articles and book, which are incorporated herein byreference, may be of interest:

-   -   Levy M N et al., in “Parasympathetic Control of the Heart,”        Nervous Control of Vascular Function, Randall W C ed., Oxford        University Press (1984)    -   Levy M N et al. ed., Vagal Control of the Heart: Experimental        Basis and Clinical Implications (The Bakken Research Center        Series Volume 7), Futura Publishing Company, Inc., Armonk, N.Y.        (1993)    -   Randall W C ed., Neural Regulation of the Heart, Oxford        University Press (1977), particularly pages 100-106.    -   Armour J A et al. eds., Neurocardiology, Oxford University Press        (1994)    -   Perez M G et al., “Effect of stimulating non-myelinated vagal        axon on atrio-ventricular conduction and left ventricular        function in anaesthetized rabbits,”Auton Neurosco 86 (2001)    -   Jones, J F X et al., “Heart rate responses to selective        stimulation of cardiac vagal C fibres in anaesthetized cats,        rats and rabbits,” J Physiol 489 (Pt 1):203-14 (1995)    -   Wallick D W et al., “Effects of ouabain and vagal stimulation on        heart rate in the dog,” Cardiovasc. Res., 18(2):75-9 (1984)    -   Martin P J et al., “Phasic effects of repetitive vagal        stimulation on atrial contraction,” Circ. Res. 52(6):657-63        (1983)    -   Wallick D W et al., “Effects of repetitive bursts of vagal        activity on atrioventricular junctional rate in dogs,” Am J        Physiol 237(3):H275-81 (1979)    -   Fuster V and Ryden L E et al., “ACC/AHA/ESC Practice        Guidelines—Executive Summary,” J Am Coll Cardiol 38(4):1231-65        (2001)    -   Fuster V and Ryden L E et al., “ACC/AHA/ESC Practice        Guidelines—Full Text,” J Am Coll Cardiol 38(4):1266i-1266lxx        (2001)    -   Morady F et al., “Effects of resting vagal tone on accessory        atrioventricular connections,” Circulation 81(1):86-90 (1990)    -   Waninger M S et al., “Electrophysiological control of        ventricular rate during atrial fibrillation,” PACE 23:1239-1244        (2000)    -   Wijffels M C et al., “Electrical remodeling due to atrial        fibrillation in chronically instrumented conscious goats: roles        of neurohumoral changes, ischemia, atrial stretch, and high rate        of electrical activation,” Circulation 96(10):3710-20 (1997)    -   Wijffels M C et al., “Atrial fibrillation begets atrial        fibrillation,” Circulation 92:1954-1968 (1995)    -   Goldberger A L et al., “Vagally-mediated atrial fibrillation in        dogs: conversion with bretylium tosylate,” Int J Cardiol        13(1):47-55 (1986)    -   Takei M et al., “Vagal stimulation prior to atrial rapid pacing        protects the atrium from electrical remodeling in anesthetized        dogs,” Jpn Circ J 65(12):1077-81 (2001)    -   Friedrichs G S, “Experimental models of atrial        fibrillation/flutter,” J Pharmacological and Toxicological        Methods 43:117-123 (2000)    -   Hayashi H et al., “Different effects of class Ic and III        antiarrhythmic drugs on vagotonic atrial fibrillation in the        canine heart,” Journal of Cardiovascular Pharmacology 31:101-107        (1998)    -   Morillo C A et al., “Chronic rapid atrial pacing. Structural,        functional, and electrophysiological characteristics of a new        model of sustained atrial fibrillation,” Circulation        91:1588-1595 (1995)    -   Lew S J et al., “Stroke prevention in elderly patients with        atrial fibrillation,” Singapore Med J 43(4):198-201 (2002)    -   Higgins C B, “Parasympathetic control of the heart,”Pharmacol.        Rev. 25:120-155 (1973)    -   Hunt R, “Experiments on the relations of the inhibitory to the        accelerator nerves of the heart,” J. Exptl. Med. 2:151-179        (1897)    -   Billette J et al., “Roles of the AV junction in determining the        ventricular response to atrial fibrillation,” Can J Physiol        Pharamacol 53(4)575-85 (1975)    -   Stramba-Badiale M et al., “Sympathetic-Parasympathetic        Interaction and Accentuated Antagonism in Conscious Dogs,”        American Journal of Physiology 260 (2Pt 2):H335-340 (1991)    -   Garrigue S et al., “Post-ganglionic vagal stimulation of the        atrioventricular node reduces ventricular rate during atrial        fibrillation,” PACE 21(4), 878 (Part II) (1998)    -   Kwan H et al., “Cardiovascular adverse drug reactions during        initiation of antiarrhythmic therapy for atrial fibrillation,”        Can J Hosp Pharm 54:10-14 (2001)    -   Jidéus L, “Atrial fibrillation after coronary artery bypass        surgery: A study of causes and risk factors,” Acta Universitatis        Upsaliensis, Uppsala, Sweden (2001)    -   Borovikova L V et al., “Vagus nerve stimulation attenuates the        systemic inflammatory response to endotoxin,” Nature        405(6785):458-62 (2000)    -   Wang H et al., “Nicotinic acetylcholine receptor alpha-7 subunit        is an essential regulator of inflammation,” Nature 421:384-388        (2003)    -   Vanoli E et al., “Vagal stimulation and prevention of sudden        death in conscious dogs with a healed myocardial infarction,”        Circ Res 68(5):1471-81 (1991)    -   De Ferrari G M, “Vagal reflexes and survival during acute        myocardial ischemia in conscious dogs with healed myocardial        infarction,” Am J Physiol 261(1 Pt 2):H63-9 (1991)    -   Li D et al., “Promotion of Atrial Fibrillation by Heart Failure        in Dogs: Atrial Remodeling of a Different Sort,” Circulation        100(1):87-95 (1999)    -   Feliciano L et al., “Vagal nerve stimulation during muscarinic        and beta-adrenergic blockade causes significant coronary artery        dilation,” Cardiovasc Res 40(1):45-55 (1998)

Heart rate variability is considered an important determinant of cardiacfunction. Heart rate normally fluctuates within a normal range in orderto accommodate constantly changing physiological needs. For example,heart rate increases during waking hours, exertion, and inspiration, anddecreases during sleeping, relaxation, and expiration. Tworepresentations of heart rate variability are commonly used: (a) thestandard deviation of beat-to-beat RR interval differences within acertain time window (i.e., variability in the time domain), and (b) themagnitude of variability as a function of frequency (i.e., variabilityin the frequency domain).

Short-term (beat-to-beat) variability in heart rate represents fast,high-frequency (HF) changes in heart rate. For example, the changes inheart rate associated with breathing are characterized by a frequency ofbetween about 0.15 and about 0.4 Hz (corresponding to a time constantbetween about 2.5 and 7 seconds). Low-frequency (LF) changes in heartrate (for example, blood pressure variations) are characterized by afrequency of between about 0.04 and about 0.15 Hz (corresponding to atime constant between about 7 and 25 seconds). Very-low-frequency (VLF)changes in heart rate are characterized by a frequency of between about0.003 and about 0.04 Hz (0.5 to 5 minutes). Ultra-low-frequency (ULF)changes in heart rate are characterized by a frequency of between about0.0001 and about 0.003 Hz (5 minutes to 2.75 hours). A commonly usedindicator of heart rate variability is the ratio of HF power to LFpower.

High heart rate variability (especially in the high frequency range, asdescribed hereinabove) is generally correlated with a good prognosis inconditions such as ischemic heart disease and heart failure. In otherconditions, such as atrial fibrillation, increased heart ratevariability in an even higher frequency range can cause a reduction incardiac efficiency by producing beats that arrive too quickly (when theventricle is not optimally filled) and beats that arrive too late (whenthe ventricle is fully filled and the pressure is too high).

Kamath et al., in “Effect of vagal nerve electrostimulation on the powerspectrum of heart rate variability in man,” Pacing Clin Electrophysiol15:235-43 (1992), describe an increase in the ratio of low frequency tohigh frequency components of the peak power spectrum of heart ratevariability during a period without vagal stimulation, compared toperiods with vagal stimulation. Iwao et al., in “Effect of constant andintermittent vagal stimulation on the heart rate and heart ratevariability in rabbits,” Jpn J Physiol 50:33-9 (2000), describe nochange in heart rate variability caused by respiration in all modes ofstimulation with respect to baseline data. Each of these articles isincorporated herein by reference.

The following articles, which are incorporated herein by reference, maybe of interest:

-   -   Kleiger R E et al., “Decreased heart rate variability and its        association with increased mortality after myocardial        infarction,” Am J Cardiol 59: 256-262 (1987)    -   Akselrod S et al., “Power spectrum analysis of heart rate        fluctuation: a quantitative probe of beat-to-beat beat        cardiovascular control,” Science 213: 220-222 (1981)

A number of patents describe techniques for treating arrhythmias and/orischemia by, at least in part, stimulating the vagus nerve. Arrhythmiasin which the heart rate is too fast include fibrillation, flutter andtachycardia. Arrhythmia in which the heart rate is too slow is known asbradyarrhythmia. U.S. Pat. No. 5,700,282 to Zabara, which isincorporated herein by reference, describes techniques for stabilizingthe heart rhythm of a patient by detecting arrhythmias and thenelectronically stimulating the vagus and cardiac sympathetic nerves ofthe patient. The stimulation of vagus efferents directly causes theheart rate to slow down, while the stimulation of cardiac sympatheticnerve efferents causes the heart rate to quicken.

U.S. Pat. No. 5,330,507 to Schwartz, which is incorporated herein byreference, describes a cardiac pacemaker for preventing or interruptingtachyarrhythmias and for applying pacing therapies to maintain the heartrhythm of a patient within acceptable limits. The device automaticallystimulates the right or left vagus nerves as well as the cardiac tissuein a concerted fashion dependent upon need. Continuous and/or phasicelectrical pulses are applied. Phasic pulses are applied in a specificrelationship with the R-wave of the ECG of the patient.

European Patent Application EP 0 688 577 to Holmström et al., which isincorporated herein by reference, describes a device to treat atrialtachyarrhythmia by detecting arrhythmia and stimulating aparasympathetic nerve that innervates the heart, such as the vagusnerve.

U.S. Pat. Nos. 5,690,681 and 5,916,239 to Geddes et al., which areincorporated herein by reference, describe closed-loop,variable-frequency, vagal-stimulation apparatus for control ofventricular rate during atrial fibrillation. The apparatus stimulatesthe left vagus nerve, and automatically and continuously adjusts thevagal stimulation frequency as a function of the difference betweenactual and desired ventricular excitation rates. In an alternativeembodiment, the apparatus automatically adjusts the vagal stimulationfrequency as a function of the difference between ventricular excitationrate and arterial pulse rate in order to eliminate or minimize pulsedeficit.

U.S. Pat. No. 5,203,326 to Collins, which is incorporated herein byreference, describes a pacemaker which detects a cardiac abnormality andresponds with electrical stimulation of the heart combined with vagusnerve stimulation. The vagal stimulation frequency is progressivelyincreased in one-minute intervals, and, for the pulse delivery rateselected, the heart rate is described as being slowed to a desired,stable level by increasing the pulse current.

U.S. Pat. No. 6,511,500 to Rahme, which is incorporated herein byreference, describes various aspects of the effects of autonomic nervoussystem tone on atrial arrhythmias, and its interaction with class IIIantiarrhythmic drug effects. The significance of sympathetic andparasympathetic activation are described as being evaluated bydetermining the effects of autonomic nervous system using vagal andstellar ganglions stimulation, and by using autonomic nervous systemneurotransmitters infusion (norepinephrine, acetylcholine).

U.S. Pat. No. 5,199,428 to Obel et al., which is incorporated herein byreference, describes a cardiac pacemaker for detecting and treatingmyocardial ischemia. The device automatically stimulates the vagalnervous system as well as the cardiac tissue in a concerted fashion inorder to decrease cardiac workload and thereby protect the myocardium.

U.S. Pat. No. 5,334,221 to Bardy and U.S. Pat. No. 5,356,425 to Bardy etal., which are incorporated herein by reference, describe a stimulatorfor applying stimulus pulses to the AV nodal fat pad in response to theheart rate exceeding a predetermined rate, in order to reduce theventricular rate. The device also includes a cardiac pacemaker whichserves to pace the ventricle in the event that the ventricular rate islowered below a pacing rate, and provides for feedback control of thestimulus parameters applied to the AV nodal fat pad, as a function ofthe determined effect of the stimulus pulses on the heart rate.

U.S. Pat. No. 5,522,854 to Ideker et al., which is incorporated hereinby reference, describes techniques for preventing arrhythmia bydetecting a high risk of arrhythmia and then stimulating afferent nervesto prevent the arrhythmia.

U.S. Pat. No. 6,434,424 to Igel et al., which is incorporated herein byreference, describes a pacing system with a mode switching feature andventricular rate regularization function adapted to stabilize orregularize ventricular heart rate during chronic or paroxysmal atrialtachyarrhythmia.

U.S. Patent Application Publication 2002/0120304 to Mest, which isincorporated herein by reference, describes a method for regulating theheart rate of a patient by inserting into a blood vessel of the patienta catheter having an electrode at its distal end, and directing thecatheter to an intravascular location so that the electrode is adjacentto a selected cardiac sympathetic or parasympathetic nerve.

U.S. Pat. Nos. 6,006,134 and 6,266,564 to Hill et al., which areincorporated herein by reference, describe an electro-stimulation deviceincluding a pair of electrodes for connection to at least one locationin the body that affects or regulates the heartbeat.

PCT Publication WO 02/085448 to Foreman et al., which is incorporatedherein by reference, describes a method for protecting cardiac functionand reducing the impact of ischemia on the heart, by electricallystimulating a neural structure capable of carrying the predeterminedelectrical signal from the neural structure to the “intrinsic cardiacnervous system,” which is defined and described therein.

U.S. Pat. No. 5,243,980 to Mehra, which is incorporated herein byreference, describes techniques for discrimination between ventricularand supraventricular tachycardia. In response to the detection of theoccurrence of a tachycardia, stimulus pulses are delivered to one orboth of the SA and AV nodal fat pads. The response of the heart rhythmto these stimulus pulses is monitored. Depending upon the change or lackof change in the heart rhythm, a diagnosis is made as to the origin ofthe tachycardia.

U.S. Pat. No. 5,658,318 to Stroetmann et al., which is incorporatedherein by reference, describes a device for detecting a state ofimminent cardiac arrhythmia in response to activity in nerve signalsconveying information from the autonomic nerve system to the heart. Thedevice comprises a sensor adapted to be placed in an extracardiacposition and to detect activity in at least one of the sympathetic andvagus nerves.

U.S. Pat. No. 6,292,695 to Webster, Jr. et al., which is incorporatedherein by reference, describes a method for controlling cardiacfibrillation, tachycardia, or cardiac arrhythmia by the use of acatheter comprising a stimulating electrode, which is placed at anintravascular location. The electrode is connected to a stimulatingmeans, and stimulation is applied across the wall of the vessel,transvascularly, to a sympathetic or parasympathetic nerve thatinnervates the heart at a strength sufficient to depolarize the nerveand effect the control of the heart.

U.S. Pat. No. 6,134,470 to Hartlaub, which is incorporated herein byreference, describes an implantable anti-arrhythmia system whichincludes a spinal cord stimulator coupled to an implantable heart rhythmmonitor. The monitor is adapted to detect the occurrence oftachyarrhythmias or of precursors thereto and, in response, trigger theoperation of the spinal cord stimulator in order to prevent occurrencesof tachyarrhythmias and/or as a stand-alone therapy for termination oftachyarrhythmias and/or to reduce the level of aggressiveness requiredof an additional therapy such as antitachycardia pacing, cardioversionor defibrillation.

A number of patents and articles describe other methods and devices forstimulating nerves to achieve a desired effect. Often these techniquesinclude a design for an electrode or electrode cuff.

U.S. Patent Publication 2003/0050677 to Gross et al., which is assignedto the assignee of the present patent application and is incorporatedherein by reference, describes apparatus for applying current to anerve. A cathode is adapted to be placed in a vicinity of a cathodiclongitudinal site of the nerve and to apply a cathodic current to thenerve. A primary inhibiting anode is adapted to be placed in a vicinityof a primary anodal longitudinal site of the nerve and to apply aprimary anodal current to the nerve. A secondary inhibiting anode isadapted to be placed in a vicinity of a secondary anodal longitudinalsite of the nerve and to apply a secondary anodal current to the nerve,the secondary anodal longitudinal site being closer to the primaryanodal longitudinal site than to the cathodic longitudinal site.

U.S. Pat. No. 4,608,985 to Crish et al. and U.S. Pat. No. 4,649,936 toUngar et al., which are incorporated herein by reference, describeelectrode cuffs for selectively blocking orthodromic action potentialspassing along a nerve trunk, in a manner intended to avoid causing nervedamage.

PCT Patent Publication WO 01/10375 to Felsen et al., which isincorporated herein by reference, describes apparatus for modifying theelectrical behavior of nervous tissue. Electrical energy is applied withan electrode to a nerve in order to selectively inhibit propagation ofan action potential.

U.S. Pat. No. 5,755,750 to Petruska et al., which is incorporated hereinby reference, describes techniques for selectively blocking differentsize fibers of a nerve by applying direct electric current between ananode and a cathode that is larger than the anode. The current appliedto the electrodes blocks nerve transmission, but, as described, does notactivate the nerve fibers in either direction.

The following articles, which are incorporated herein by reference, maybe of interest:

-   -   Ungar I J et al., “Generation of unidirectionally propagating        action potentials using a monopolar electrode cuff,” Annals of        Biomedical Engineering, 14:437-450 (1986)    -   Sweeney J D et al., “An asymmetric two electrode cuff for        generation of unidirectionally propagated action potentials,”        IEEE Transactions on Biomedical Engineering, vol. BME-33(6)        (1986)    -   Sweeney J D et al., “A nerve cuff technique for selective        excitation of peripheral nerve trunk regions,” IEEE Transactions        on Biomedical Engineering, 37(7) (1990)    -   Naples G G et al., “A spiral nerve cuff electrode for peripheral        nerve stimulation,” by IEEE Transactions on Biomedical        Engineering, 35(11) (1988)    -   van den Honert C et al., “Generation of unidirectionally        propagated action potentials in a peripheral nerve by brief        stimuli,” Science, 206:1311-1312 (1979)    -   van den Honert C et al., “A technique for collision block of        peripheral nerve: Single stimulus analysis,” MP-11, IEEE Trans.        Biomed. Eng. 28:373-378 (1981)    -   van den Honert C et al., “A technique for collision block of        peripheral nerve: Frequency dependence,” MP-12, IEEE Trans.        Biomed. Eng. 28:379-382 (1981)    -   Rijkhoff N J et al., “Acute animal studies on the use of anodal        block to reduce urethral resistance in sacral root stimulation,”        IEEE Transactions on Rehabilitation Engineering, 2(2):92 (1994)    -   Mushahwar V K et al., “Muscle recruitment through electrical        stimulation of the lumbo-sacral spinal cord,” IEEE Trans Rehabil        Eng, 8(1):22-9 (2000)    -   Deurloo K E et al., “Transverse tripolar stimulation of        peripheral nerve: a modelling study of spatial selectivity,” Med        Biol Eng Comput, 36(1):66-74 (1998)    -   Tarver W B et al., “Clinical experience with a helical bipolar        stimulating lead,” Pace, Vol. 15, October, Part II (1992)    -   Manfredi M, “Differential block of conduction of larger fibers        in peripheral nerve by direct current,” Arch. Ital. Biol.,        108:52-71 (1970)

In physiological muscle contraction, nerve fibers are recruited in theorder of increasing size, from smaller-diameter fibers to progressivelylarger-diameter fibers. In contrast, artificial electrical stimulationof nerves using standard techniques recruits fibers in a larger- tosmaller-diameter order, because larger-diameter fibers have a lowerexcitation threshold. This unnatural recruitment order causes musclefatigue and poor force gradation. Techniques have been explored to mimicthe natural order of recruitment when performing artificial stimulationof nerves to stimulate muscles.

Fitzpatrick et al., in “A nerve cuff design for the selective activationand blocking of myelinated nerve fibers,” Ann. Conf. of the IEEE Eng. inMedicine and Biology Soc, 13(2), 906 (1991), which is incorporatedherein by reference, describe a tripolar electrode used for musclecontrol. The electrode includes a central cathode flanked on itsopposite sides by two anodes. The central cathode generates actionpotentials in the motor nerve fiber by cathodic stimulation. One of theanodes produces a complete anodal block in one direction so that theaction potential produced by the cathode is unidirectional. The otheranode produces a selective anodal block to permit passage of the actionpotential in the opposite direction through selected motor nerve fibersto produce the desired muscle stimulation or suppression.

The following articles, which are incorporated herein by reference, maybe of interest:

-   -   Rijkhoff N J et al., “Orderly recruitment of motoneurons in an        acute rabbit model,” Ann. Conf. of the IEEE Eng., Medicine and        Biology Soc., 20(5):2564 (1998)    -   Rijkhoff N J et al., “Selective stimulation of small diameter        nerve fibers in a mixed bundle,” Proceedings of the Annual        Project Meeting Sensations/Neuros and Mid-Term Review Meeting on        the TMR-Network Neuros, Apr. 21-23, 1999, pp. 20-21 (1999)    -   Baratta R et al., “Orderly stimulation of skeletal muscle motor        units with tripolar nerve cuff electrode,” IEEE Transactions on        Biomedical Engineering, 36(8):836-43 (1989)    -   Levy M N, Blattberg B., “Effect of vagal stimulation on the        overflow of norepinephrine into the coronary sinus during        sympathetic nerve stimulation in the dog,” Circ Res 1976        February; 38(2):81-4    -   Lavallee et al. “Muscarinic inhibition of endogenous myocardial        catecholamine liberation in the dog,” Can J Physiol Pharmacol        1978 August; 56(4):642-9    -   Mann D L, Kent R L, Parsons B, Cooper G, “Adrenergic effects on        the biology of the adult mammalian cardiocyte,” Circulation 1992        February; 85(2):790-804    -   Mann D L, “Basic mechanisms of disease progression in the        failing heart: role of excessive adrenergic drive,” Prog        Cardiovasc Dis 1998 July-August; 41(1suppl 1):1-8    -   Barzilai A, Daily D, Zilkha-Falb R, Ziv I, Offen D, Melamed E,        Sirv A, “The molecular mechanisms of dopamine toxicity,” Adv        Neurol 2003; 91:73-82

The following articles, which are incorporated herein by reference,describe techniques using point electrodes to selectively exciteperipheral nerve fibers:

-   -   Grill W M et al., “Inversion of the current-distance        relationship by transient depolarization,” IEEE Trans Biomed        Eng, 44(1):1-9 (1997)    -   Goodall E V et al., “Position-selective activation of peripheral        nerve fibers with a cuff electrode,” IEEE Trans Biomed Eng,        43(8):851-6 (1996)    -   Veraart C et al., “Selective control of muscle activation with a        multipolar nerve cuff electrode,” IEEE Trans Biomed Eng,        40(7):640-53 (1993)

As defined by Rattay, in the article, “Analysis of models forextracellular fiber stimulation,” IEEE Transactions on BiomedicalEngineering, Vol. 36, no. 2, p. 676, 1989, which is incorporated hereinby reference, the activation function (AF) is the second spatialderivative of the electric potential along an axon. In the region wherethe activation function is positive, the axon depolarizes, and in theregion where the activation function is negative, the axonhyperpolarizes. If the activation function is sufficiently positive,then the depolarization will cause the axon to generate an actionpotential; similarly, if the activation function is sufficientlynegative, then local blocking of action potentials transmission occurs.The activation function depends on the current applied, as well as thegeometry of the electrodes and of the axon.

For a given electrode geometry, the equation governing the electricalpotential is:∇(σ∇U)=4πj,

-   -   where U is the potential, σ is the conductance tensor specifying        the conductance of the various materials (electrode housing,        axon, intracellular fluid, etc.), and j is a scalar function        representing the current source density specifying the locations        of current injection.

SUMMARY OF THE INVENTION

In embodiments of the present invention, apparatus for treating a heartcondition comprises a multipolar electrode device that is applied to aportion of a vagus nerve that innervates the heart of a patient.Typically, the system is configured to treat heart failure and/or heartarrhythmia, such as atrial fibrillation or tachycardia. A control unittypically drives the electrode device to (i) apply signals to induce thepropagation of efferent action potentials towards the heart, and (ii)suppress artificially-induced afferent and efferent action potentials,in order to minimize any unintended side effect of the signalapplication.

The control unit typically suppresses afferent action potentials inducedby the cathodic current by inhibiting essentially all or a largefraction of fibers using anodal current (“afferent anodal current”) froma second set of one or more anodes (the “afferent anode set”). Theafferent anode set is typically placed between the central cathode andthe edge of the electrode device closer to the brain (the “afferentedge”), to block a large fraction of fibers from conveying signals inthe direction of the brain during application of the afferent anodalcurrent.

In some embodiments of the present invention, the cathodic current isapplied with an amplitude sufficient to induce action potentials inlarge- and medium-diameter fibers (e.g., A- and B-fibers), butinsufficient to induce action potentials in small-diameter fibers (e.g.,C-fibers). Simultaneously, a small anodal current is applied in order toinhibit action potentials induced by the cathodic current in thelarge-diameter fibers (e.g., A-fibers). This combination of cathodic andanodal current generally results in the stimulation of medium-diameterfibers (e.g., B-fibers) only. At the same time, a portion of theafferent action potentials induced by the cathodic current are blocked,as described above. By not stimulating large-diameter fibers, suchstimulation generally avoids adverse effects sometimes associated withrecruitment of such large fibers, such as dyspnea and hoarseness.Stimulation of small-diameter fibers is avoided because these fiberstransmit pain sensations and are important for regulation of reflexessuch as respiratory reflexes.

In some embodiments of the present invention, the efferent anode setcomprises a plurality of anodes. Application of the efferent anodalcurrent in appropriate ratios from the plurality of anodes in theseembodiments generally minimizes the “virtual cathode effect,” wherebyapplication of too large an anodal current creates a virtual cathode,which stimulates rather than blocks fibers. When such techniques are notused, the virtual cathode effect generally hinders blocking ofsmaller-diameter fibers, because a relatively large anodal current istypically necessary to block such fibers, and this same large anodalcurrent induces the virtual cathode effect. Likewise, the afferent anodeset typically comprises a plurality of anodes in order to minimize thevirtual cathode effect in the direction of the brain.

In some embodiments of the present invention, the efferent and afferentanode sets each comprise exactly one electrode, which are directlyelectrically coupled to each other. The cathodic current is applied withan amplitude sufficient to induce action potentials in large- andmedium-diameter fibers (e.g., A- and B-fibers), but insufficient toinduce action potentials in small-diameter fibers (e.g., C-fibers).Simultaneously, an anodal current is applied in order to inhibit actionpotentials induced by the cathodic current in the large-diameter fibers(e.g., A-fibers), but not in the small- and medium-diameter fibers(e.g., B- and C-fibers). This combination of cathodic and anodal currentgenerally results in the stimulation of medium-diameter fibers (e.g.,B-fibers) only.

Typically, parasympathetic stimulation of the vagus nerve is appliedresponsive to one or more sensed physiological parameters or otherparameters, such as heart rate, electrocardiogram (ECG), blood pressure,indicators of cardiac contractility, cardiac output, norepinephrineconcentration, baroreflex sensitivity, or motion of the patient.Typically, stimulation is applied in a closed-loop system in order toachieve and maintain a desired heart rate responsive to one or more suchsensed parameters.

In some embodiments of the present invention, vagal stimulation isapplied in a burst (i.e., a series of pulses). The application of theburst in each cardiac cycle typically commences after a variable delayafter a detected R-wave, P-wave, or other feature of an ECG. The delayis typically calculated in real time using a function, the inputs ofwhich include one or more pre-programmed but updateable constants andone or more sensed parameters, such as the R-R interval between cardiaccycles and/or the P-R interval. Alternatively or additionally, a lookuptable of delays is used to determine in real time the appropriate delayfor each application of pulses, based on the one or more sensedparameters.

In some embodiments of the present invention, the control unit isconfigured to drive the electrode device to stimulate the vagus nerve soas to reduce the heart rate of the subject towards a target heart rate.Parameters of stimulation are varied in real time in order to vary theheart-rate-lowering effects of the stimulation. In embodiments of thepresent invention in which the stimulation is applied in a series ofpulses that are synchronized with the cardiac cycle of the subject, suchas described hereinabove, parameters of such pulse series typicallyinclude, but are not limited to: (a) timing of the stimulation withinthe cardiac cycle, (b) pulse duration (width), (c) pulse repetitioninterval, (d) pulse period, (e) number of pulses per burst, alsoreferred to herein as “pulses per trigger” (PPT), (f) amplitude, (g)duty cycle, (h) choice of vagus nerve, and (i) “on”/“off” ratio andtiming (i.e., during intermittent operation).

In some embodiments of the present invention, the control unit isconfigured to drive the electrode device to stimulate the vagus nerve soas to modify heart rate variability of the subject. For someapplications, the control unit is configured to apply stimulation withparameters that tend to or that are selected to reduce heart ratevariability, while for other applications parameters are used that tendto or that are selected to increase variability. For some applications,the parameters of the stimulation are selected to both reduce the heartrate of the subject and heart rate variability of the subject. For otherapplications, the parameters are selected to reduce heart ratevariability while substantially not reducing the heart rate of thesubject. For some applications, the control unit is configured to drivethe electrode device to stimulate the vagus nerve so as to modify heartrate variability in order to treat a condition of the subject.

Advantageously, the techniques described herein generally enablerelatively fine control of the level of stimulation of the vagus nerve,by imitating the natural physiological smaller-to-larger diameterrecruitment order of nerve fibers. This recruitment order allowsimproved and more natural control over the heart rate. Such fine controlis particularly advantageous when applied in a closed-loop system,wherein such control results in smaller changes in heart rate and lowerlatencies in the control loop, which generally contribute to greaterloop stability and reduced loop stabilization time.

“Vagus nerve,” and derivatives thereof, as used in the specification andthe claims, is to be understood to include portions of the left vagusnerve, the right vagus nerve, and branches of the vagus nerve such asthe superior cardiac nerve, superior cardiac branch, and inferiorcardiac branch. Similarly, stimulation of the vagus nerve is describedherein by way of illustration and not limitation, and it is to beunderstood that stimulation of other autonomic nerves, including nervesin the epicardial fat pads, for treatment of heart conditions or otherconditions, is also included within the scope of the present invention.

“Heart failure,” as used in the specification and the claims, is to beunderstood to include all forms of heart failure, including ischemicheart failure, non-ischemic heart failure, and diastolic heart failure.

There is therefore provided, in accordance with an embodiment of thepresent invention, apparatus for treating a heart condition of asubject, including:

an electrode device, adapted to be coupled to a vagus nerve of thesubject; and

a control unit, adapted to:

drive the electrode device to apply to the vagus nerve a stimulatingcurrent, which is capable of inducing action potentials in a therapeuticdirection in a first set and a second set of nerve fibers of the vagusnerve, and

drive the electrode device to apply to the vagus nerve an inhibitingcurrent, which is capable of inhibiting the induced action potentialstraveling in the therapeutic direction in the second set of nervefibers, the nerve fibers in the second set having generally largerdiameters than the nerve fibers in the first set.

Typically, the therapeutic direction is an efferent therapeuticdirection towards a heart of the subject. Alternatively or additionally,the therapeutic direction is an afferent therapeutic direction towards abrain of the subject.

In an embodiment, the control unit increases a number of actionpotentials traveling in the therapeutic direction by decreasing anamplitude of the applied inhibiting current, and/or decreases a numberof action potentials traveling in the therapeutic direction byincreasing an amplitude of the applied inhibiting current.

In an embodiment, the heart condition includes heart failure and/orcardiac arrhythmia, and the apparatus is adapted to treat the heartcondition.

Optionally, the apparatus includes an override, adapted to be used bythe subject so as to influence the application by the electrode deviceof the stimulating and inhibiting currents.

In an embodiment, the apparatus includes a pacemaker, and the controlunit is adapted to drive the pacemaker to apply pacing pulses to a heartof the subject. Alternatively, the apparatus includes an implantablecardioverter defibrillator (ICD), and the control unit is adapted todrive the ICD to apply energy to a heart of the subject.

Typically, the control unit is adapted to drive the electrode device toapply the stimulating current and/or the inhibiting current in a seriesof pulses.

In an embodiment, the control unit receives an electrical signal fromthe electrode device, and drives the electrode device to regulate thestimulating and/or inhibiting current responsive to the electricalsignal.

Typically, the electrode device includes a cathode, adapted to apply thestimulating current, and a primary set of anodes, which applies theinhibiting current. For some applications, the primary set of anodesincludes a primary anode and a secondary anode, disposed so that theprimary anode is located between the secondary anode and the cathode,and the secondary anode applies a current with an amplitude less thanabout one half an amplitude of a current applied by the primary anode.

Typically, the control unit is adapted to drive the electrode device toapply the stimulating current so as to regulate a heart rate of thesubject. For some applications, the control unit is adapted to drive theelectrode device to regulate an amplitude of the stimulating current soas to regulate the heart rate of the subject.

Alternatively or additionally, the control unit drives the electrodedevice to apply the inhibiting current so as to regulate a heart rate ofthe subject. In this case, the control unit typically drives theelectrode device to regulate an amplitude of the inhibiting current soas to regulate the heart rate of the subject.

Typically, the control unit is adapted to drive the electrode device toapply the stimulating and inhibiting currents in a series of pulses. Forsome applications, the control unit:

-   -   drives the electrode device to apply the stimulating and        inhibiting currents in a series of about one to 20 pulses,    -   configures the pulses to have a duration of between about one        and three milliseconds, and/or    -   drives the electrode device to apply the stimulating and        inhibiting currents in the series of pulses over a period of        between about one and about 200 milliseconds.

Typically, the control unit drives the electrode device to apply thestimulating and inhibiting currents in the series of pulses so as toregulate a heart rate of the subject. For some applications, the controlunit regulates the number of pulses in the series of pulses so as toregulate the heart rate of the subject. Optionally, the control unitregulates a duration of each pulse so as to regulate the heart rate ofthe subject. Optionally, the control unit varies a length of a period ofapplication of the series of pulses so as to regulate the heart rate ofthe subject.

In an embodiment, the control unit drives the electrode device to applyto the vagus nerve a second inhibiting current, which is capable ofinhibiting device-induced action potentials traveling in anon-therapeutic direction opposite the therapeutic direction in thefirst and second sets of nerve fibers.

Typically, the control unit drives the electrode device to apply thesecond inhibiting current to the vagus nerve at a primary and asecondary location, the primary location located between the secondarylocation and an application location of the stimulating current, and toapply at the secondary location a current with an amplitude less thanabout one half an amplitude of a current applied at the primarylocation.

In an embodiment, the apparatus includes a sensor unit, and the controlunit is adapted to receive at least one sensed parameter from the sensorunit, and to drive the electrode device to apply the stimulating andinhibiting currents responsive to the at least one sensed parameter.

Typically, the control unit is programmed with a predetermined targetheart rate, or is adapted to determine a target heart rate of thesubject responsive to the at least one sensed parameter, and the controlunit is adapted to drive the electrode device to apply the stimulatingand inhibiting currents so as to adjust a heart rate of the subjecttowards the target heart rate.

The sensor unit may include one or more of the following sensors, inwhich case the control unit receives the at least one sensed parameterfrom the following one or more sensors:

-   -   a blood pressure sensor,    -   a left ventricular pressure (LVP) sensor,    -   an accelerometer (in which case, the at least one sensed        parameter includes motion of the subject),    -   a detector of norepinephrine concentration in the subject,    -   an ECG sensor,    -   a respiration sensor, and/or    -   an impedance cardiography sensor.

Alternatively or additionally, the at least one sensed parameterincludes an indicator of decreased cardiac contractility, an indicatorof cardiac output, and/or an indicator of a time derivative of a LVP,and the control unit receives the indicator.

In an embodiment, the sensor unit includes an electrocardiogram (ECG)monitor, the at least one sensed parameter includes an ECG value, andthe control unit receives the at least one sensed parameter from the ECGmonitor.

Typically, the at least one sensed parameter includes an ECG readingindicative of a presence of arrhythmia, and the control unit is adaptedto receive the at least one sensed parameter from the ECG monitor.Optionally, the at least one sensed parameter includes an indication ofa heart rate of the subject, and the control unit is adapted to receivethe indication of the heart rate. Further optionally, the at least onesensed parameter includes indications of a plurality of heart rates ofthe subject at a respective plurality of points in time, and the controlunit is adapted to receive the at least one sensed parameter and todetermine a measure of variability of heart rate responsive thereto.

In an embodiment, the sensor unit is adapted to sense an initiationphysiological parameter and a termination physiological parameter of thesubject, and the control unit is adapted to drive the electrode deviceto apply the stimulating and inhibiting currents to the vagus nerveafter a delay, to initiate the delay responsive to the sensing of theinitiation physiological parameter, and to set a length of the delayresponsive to the termination physiological parameter.

Typically, the control unit is adapted to determine a target heart rateof the subject responsive to the at least one sensed parameter, and thecontrol unit is adapted to set the delay so as to adjust the heart ratetowards the target heart rate.

Optionally, the termination physiological parameter includes anatrioventricular (AV) delay of the subject, and the control unit isadapted to set the length of the delay responsive to the AV delay.

Typically, the sensor unit includes an electrocardiogram (ECG) monitor,and the initiation physiological parameter includes a P-wave or R-waveof a cardiac cycle of the subject, and wherein the control unit isadapted to initiate the delay responsive to the sensing of the P-wave orR-wave, as the case may be. Typically, the termination physiologicalparameter includes a difference in time between two features of an ECGsignal recorded by the ECG monitor, such as an R-R interval between asensing of an R-wave of a first cardiac cycle of the subject and asensing of an R-wave of a next cardiac cycle of the subject, or a P-Rinterval between a sensing of a P-wave of a cardiac cycle of the subjectand a sensing of an R-wave of the cardiac cycle, and the control unitsets the length of the delay and/or the magnitude of the stimulationresponsive to the termination physiological parameter.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for treating a heart condition of asubject, including:

a cathode, adapted to apply to a vagus nerve of the subject astimulating current which is capable of inducing action potentials inthe vagus nerve; and

a primary and a secondary anode, adapted to be disposed so that theprimary anode is located between the secondary anode and the cathode,and adapted to apply to the vagus nerve respective primary and secondaryinhibiting currents which are capable of inhibiting action potentials inthe vagus nerve.

Typically, the primary and secondary anodes are adapted to be placedbetween about 0.5 and about 2.0 millimeters apart from one another. Thesecondary anode is typically adapted to apply the secondary inhibitingcurrent with an amplitude equal to between about 2 and about 5milliamps. The secondary anode is typically adapted to apply thesecondary inhibiting current with an amplitude less than about one halfan amplitude of the primary inhibiting current applied by the primaryanode.

In an embodiment, the primary anode, the secondary anode, and/or thecathode includes a ring electrode adapted to apply a generally uniformcurrent around a circumference of the vagus nerve. Alternatively oradditionally, the primary anode, the secondary anode, and/or the cathodeincludes a plurality of discrete primary anodes, adapted to be disposedat respective positions around an axis of the vagus nerve.

Optionally, the apparatus includes a tertiary anode, adapted to bedisposed such that the secondary anode is between the tertiary anode andthe primary anode.

Typically, the electrode device includes an efferent edge, and thecathode is adapted to be disposed closer than the anodes to the efferentedge of the electrode device.

Typically, the cathode and/or the anodes are adapted to apply thestimulating current so as to regulate a heart rate of the subject.

Optionally, the cathode includes a plurality of discrete cathodes,adapted to be disposed at respective positions around an axis of thevagus nerve, so as to selectively stimulate nerve fibers of the vagusnerve responsive to the positions of the nerve fibers in the vagusnerve.

Optionally, the apparatus includes a set of one or more blocking anodes,adapted to be disposed such that the cathode is between the set ofblocking anodes and the primary anode, and adapted to apply to the vagusnerve a current which is capable of inhibiting action potentialspropagating in the vagus nerve in a direction from the cathode towardsthe set of blocking anodes.

Typically, the set of blocking anodes includes a first anode and asecond anode, adapted to be disposed such that the first anode islocated between the second anode and the cathode, and wherein the secondanode is adapted to apply a current with an amplitude less than aboutone half an amplitude of a current applied by the first anode.

Typically, the electrode device includes an afferent edge, wherein thecathode is adapted to be disposed closer than the anodes to the afferentedge of the electrode device.

Typically, the apparatus includes a cuff, and an electrically-insulatingelement coupled to an inner portion of the cuff, and the primary anodeand the cathode are adapted to be mounted in the cuff and separated fromone another by the insulating element. Typically, the primary andsecondary anodes and the cathode are recessed in the cuff so as not tobe in direct contact with the vagus nerve.

Typically, the apparatus includes a control unit, adapted to drive thecathode and the anodes to apply the respective currents to the vagusnerve, so as to treat the subject.

Typically, the cathode is adapted to apply the stimulating current andthe anodes are adapted to apply the inhibiting current so as to regulatea heart rate of the subject. Optionally, the cathode is adapted to varyan amplitude of the applied stimulating current and the anodes areadapted to vary an amplitude of the applied inhibiting current so as toregulate a heart rate of the subject.

Typically, the control unit is adapted to:

drive the electrode device to apply to the vagus nerve a stimulatingcurrent, which is capable of inducing action potentials in a therapeuticdirection in a first set and a second set of nerve fibers of the vagusnerve, and

drive the electrode device to apply to the vagus nerve an inhibitingcurrent, which is capable of inhibiting the induced action potentialstraveling in the therapeutic direction in the second set of nervefibers, the nerve fibers in the second set having generally largerdiameters than the nerve fibers in the first set.

Optionally, the termination physiological parameter includes a bloodpressure of the subject, and wherein the control unit is adapted to setthe length of the delay responsive to the blood pressure.

Typically, the sensor unit is adapted to sense a rate-setting parameterof the subject, wherein the rate-setting parameter includes a bloodpressure of the subject, and wherein the control unit is adapted toreceive the rate-setting parameter from the sensor unit and to drive theelectrode device to apply the current responsive to the rate-settingparameter.

Optionally, the rate-setting parameter includes the initiationphysiological parameter and/or the termination physiological parameter,and the control unit is adapted to drive the electrode device to applythe current responsive to the initiation physiological parameter so asto regulate the heart rate of the subject.

Typically, the control unit is adapted to set the length of the delay soas to adjust the heart rate towards the target heart rate. Optionally,the control unit is adapted to access a lookup table of delays, and toset the length of the delay using the lookup table and responsive to theinitiation and termination physiological parameters.

Typically, the initiation physiological parameter includes a P-wave,R-wave, Q-wave, S-wave, or T-wave of a cardiac cycle of the subject, andwherein the control unit is adapted to initiate the delay responsive tothe sensing of the cardiac wave.

Typically, the termination physiological parameter includes a differencein time between two features of an ECG signal recorded by the ECGmonitor, and the control unit is adapted to set the length of the delayresponsive to the difference in time between the two features. Thetermination physiological parameter may include an R-R interval betweena sensing of an R-wave of a first cardiac cycle of the subject and asensing of an R-wave of a next cardiac cycle of the subject, and whereinthe control unit is adapted to set the length of the delay responsive tothe R-R interval. Alternatively or additionally, the terminationphysiological parameter includes an average of R-R intervals sensed fora number of cardiac cycles, and wherein the control unit is adapted toset the length of the delay responsive to the average of the R-Rintervals.

Alternatively, the termination physiological parameter includes a P-Rinterval between a sensing of a P-wave of a cardiac cycle of the subjectand a sensing of an R-wave of the cardiac cycle, and wherein the controlunit is adapted to set the length of the delay responsive to the P-Rinterval. Alternatively or additionally, the termination physiologicalparameter includes an average of P-R intervals sensed for a number ofcardiac cycles, and wherein the control unit is adapted to set thelength of the delay responsive to the average of the P-R intervals.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for treating a condition of a subject, including:

an electrode device, adapted to be coupled to an autonomic nerve of thesubject; and

a control unit, adapted to:

drive the electrode device to apply to the nerve a stimulating current,which is capable of inducing action potentials in a therapeuticdirection in a first set and a second set of nerve fibers of the nerve,and

drive the electrode device to apply to the nerve an inhibiting current,which is capable of inhibiting the induced action potentials travelingin the therapeutic direction in the second set of nerve fibers, thenerve fibers in the second set having generally larger diameters thanthe nerve fibers in the first set.

Typically, the autonomic nerve includes the vagus nerve, and the controlunit is adapted to drive the electrode device to apply the stimulatingand inhibiting currents to the nerve.

Typically, the control unit is adapted to drive the electrode device toapply the stimulating and inhibiting currents to the nerve so as toaffect behavior of one of the following, so as to treat the condition:

a lung of the subject,

a heart of the subject,

an immune system of the subject, and/or

an adrenal gland of the subject.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus for treating a condition of a subject,including:

a cathode, adapted to apply to an autonomic nerve of the subject astimulating current which is capable of inducing action potentials inthe nerve; and

a primary and a secondary anode, adapted to be disposed so that theprimary anode is located between the secondary anode and the cathode,and adapted to apply to the nerve respective primary and secondaryinhibiting currents which are capable of inhibiting action potentials inthe nerve.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method for treating a heart condition of asubject, including:

applying, to a vagus nerve of the subject, a stimulating current whichis capable of inducing action potentials in a therapeutic direction in afirst set and a second set of nerve fibers of the vagus nerve; and

applying to the vagus nerve an inhibiting current which is capable ofinhibiting the induced action potentials traveling in the therapeuticdirection in the second set of nerve fibers, the nerve fibers in thesecond set having generally larger diameters than the nerve fibers inthe first set.

There is still additionally provided, in accordance with an embodimentof the present invention, a method for treating a heart condition of asubject, including:

applying, to a vagus nerve of the subject, at a stimulation location, astimulating current which is capable of inducing action potentials inthe vagus nerve, so as to treat the subject; and

applying to the vagus nerve at a primary and a secondary location, theprimary location located between the secondary location and thestimulation location, an inhibiting current which is capable ofinhibiting action potentials in the vagus nerve.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for treating a condition of a subject,including:

applying, to an autonomic nerve of the subject, a stimulating currentwhich is capable of inducing action potentials in a therapeuticdirection in a first set and a second set of nerve fibers of the nerve;and

applying to the nerve an inhibiting current which is capable ofinhibiting the induced action potentials traveling in the therapeuticdirection in the second set of nerve fibers, the nerve fibers in thesecond set having generally larger diameters than the nerve fibers inthe first set.

There is also provided, in accordance with an embodiment of the presentinvention, a method for treating a condition of a subject, including:

applying, to an autonomic nerve of the subject, at a stimulationlocation, a stimulating current which is capable of inducing actionpotentials in the nerve, so as to treat the subject; and

applying to the nerve at a primary and a secondary location, the primarylocation located between the secondary location and the stimulationlocation, an inhibiting current which is capable of inhibiting actionpotentials in the nerve.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for treating a subject, including:

an electrode device, adapted to be coupled to a vagus nerve of thesubject;

a heart rate sensor, configured to detect a heart rate of the subject,and to generate a heart rate signal responsive thereto; and

a control unit, adapted to:

receive the heart rate signal, and

responsive to determining that the heart rate is greater than athreshold value, which threshold value is greater than a normal heartrate, drive the electrode device to apply a current to the vagus nerve,and configure the current so as to reduce the heart rate of the subject.

For some applications, the control unit is adapted to configure thecurrent to include a stimulating current, which is capable of inducingaction potentials in a first set and a second set of nerve fibers of thevagus nerve, and an inhibiting current, which is capable of inhibitingthe induced action potentials traveling in the second set of nervefibers, the nerve fibers in the second set having generally largerdiameters than the nerve fibers in the first set, and the control unitis adapted to drive the electrode device to apply the stimulatingcurrent and the inhibiting current to the vagus nerve.

Alternatively or additionally, the current includes a stimulatingcurrent, which is capable of inducing action potentials in the vagusnerve, and an inhibiting current, which is capable of inhibitingdevice-induced action potentials traveling in the vagus nerve in anafferent direction toward a brain of the subject, and the control unitis adapted to drive the electrode device to apply the stimulatingcurrent and the inhibiting current to the vagus nerve.

For some applications, the vagus nerve includes small-, medium-, andlarge-diameter fibers, and the electrode device includes:

a cathode, adapted to be disposed at a cathodic site of the vagus nerve,and to apply a cathodic current to the vagus nerve which is capable ofinducing action potentials in the vagus nerve; and

-   -   an anode, adapted to be disposed at an anodal site of the vagus        nerve, and to apply to the vagus nerve an anodal current which        is capable of inhibiting action potentials in the vagus nerve,        and

the control unit is adapted to:

drive the cathode to apply to the vagus nerve the cathodic currenthaving a cathodic amplitude sufficient to induce action potentials inthe medium- and large-diameter fibers, but generally insufficient toinduce action potentials in the small-diameter fibers, and

drive the anode to apply to the vagus nerve the anodal current having ananodal amplitude sufficient to inhibit action potentials in thelarge-diameter fibers, but generally insufficient to inhibit actionpotentials in the medium-diameter fibers.

In an embodiment, the control unit is adapted to utilize a value of atleast 100 beats per minute as the threshold value.

In an embodiment, the control unit is adapted to withhold driving theelectrode device upon determining that the heart rate is less than avalue associated with bradycardia.

In an embodiment, the control unit is adapted to configure the currentso as to reduce the heart rate towards a target heart rate.

For some applications, the normal heart rate includes a normal heartrate of the subject. Alternatively, the normal heart rate includes anormal heart rate of a typical human.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the current with an amplitude of between about 2 andabout 10 milliamps.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the current in intermittent ones of a plurality ofcardiac cycles of the subject.

In an embodiment, the apparatus includes an electrode selected from thelist consisting of: an electrode for pacing the heart, and an electrodefor defibrillating the heart, and the control unit is adapted towithhold driving the electrode device to apply the current to the vagusnerve if the control unit is driving the electrode selected from thelist.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the current in respective pulse bursts in each of aplurality of cardiac cycles of the subject. The control unit may beadapted to configure each pulse of each of the bursts to have a pulseduration of between about 0.2 and about 4 milliseconds. The control unitmay be adapted to configure each of the bursts to have a pulserepetition interval of greater than about 3 milliseconds. Alternativelyor additionally, the control unit is adapted to configure at least oneof the bursts to have between about 0 and about 8 pulses.

In an embodiment, the apparatus includes an electrocardiogram (ECG)monitor, adapted to generate an ECG signal, and the control unit isadapted to receive the ECG signal, and to initiate the applying of eachburst after a delay following detection of a feature of the ECG.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus for applying current to a vagus nerve,including:

a cathode, adapted to be disposed at a cathodic site of the vagus nerveand to apply a cathodic current to the vagus nerve so as to stimulatethe vagus nerve;

a first anode, adapted to be disposed at a first anodal site of thevagus nerve; and

a second anode, directly electrically connected to the first anode, andadapted to be disposed at a second anodal site of the vagus nerve, suchthat the cathodic site is between the first anodal site and the secondanodal site.

In an embodiment, the cathode and anodes are disposed such that thecathodic site is disposed closer to the first anodal site than to thesecond anodal site.

In an embodiment, the nerve includes small-, medium-, and large-diameterfibers, and the apparatus includes a control unit, adapted to:

drive the cathode to apply to the vagus nerve the cathodic currenthaving a cathodic amplitude sufficient to induce action potentials inthe medium- and large-diameter fibers, but generally insufficient toinduce action potentials in the small-diameter fibers, and

drive the first and second anodes to apply to the vagus nerve an anodalcurrent having an anodal amplitude sufficient to inhibit actionpotentials in the large-diameter fibers, but generally insufficient toinhibit action potentials in the medium-diameter fibers.

In an embodiment, the apparatus includes:

a control unit; and

an electrode selected from the list consisting of: an electrode forpacing the heart, and an electrode for defibrillating the heart,

and the control unit is adapted to drive current through the cathode andthe first and second anodes, and the control unit is adapted to withholddriving current through the cathode and the first and second anodes ifthe control unit is driving current through the electrode selected fromthe list.

In an embodiment, the apparatus includes a control unit, adapted to:

drive the cathode to apply the cathodic current,

configure the cathodic current to induce action potentials in a firstset and a second set of nerve fibers of the vagus nerve, the nervefibers in the second set having generally larger diameters than thenerve fibers in the first set,

drive an anodal current to the first and second anodes, whereby thefirst and second anodes apply current to the vagus nerve at levelscorresponding to respective first and second anodal currents, and

configure the anodal current driven to the first and second anodes toinhibit the induced action potentials traveling in the second set ofnerve fibers.

In an embodiment, the first and second anodes are configured such that alevel of impedance between the first anode and the cathode is lower thana level of impedance between the second anode and the cathode, thecontrol unit is adapted to configure the anodal current driven to thefirst and second anodes such that the first anodal current inhibits theinduced action potentials traveling in the first set of nerve fibers,and the control unit is adapted to configure the anodal current drivento the first and second anodes to be such that the second anodal currentis generally insufficient to inhibit the induced action potentialstraveling in the first set of nerve fibers.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus for treating a subject, including:

an electrode device, adapted to be coupled to a vagus nerve of thesubject;

a sensor, configured to detect a heart rate of the subject, and togenerate a heart rate signal responsive thereto; and

a control unit including an integral feedback controller that has inputsincluding the detected heart rate and a target heart rate, the controlunit adapted to:

drive the electrode device to apply a current to the vagus nerve, and

configure the current responsive to an output of the integral feedbackcontroller, so as to reduce the heart rate of the subject toward atarget heart rate.

In an embodiment, the control unit is adapted to configure the currentto include a stimulating current, which is capable of inducing actionpotentials in a first set and a second set of nerve fibers of the vagusnerve, and an inhibiting current, which is capable of inhibiting theinduced action potentials traveling in the second set of nerve fibers,the nerve fibers in the second set having generally larger diametersthan the nerve fibers in the first set, and the control unit is adaptedto drive the electrode device to apply the stimulating current and theinhibiting current to the vagus nerve.

In an embodiment, the current includes a stimulating current, which iscapable of inducing action potentials in the vagus nerve, and aninhibiting current, which is capable of inhibiting device-induced actionpotentials traveling in the vagus nerve in an afferent direction towarda brain of the subject, and the control unit is adapted to drive theelectrode device to apply the stimulating current and the inhibitingcurrent to the vagus nerve.

In an embodiment, the vagus nerve includes small-, medium-, andlarge-diameter fibers, and the electrode device includes:

a cathode, adapted to be disposed at a cathodic site of the vagus nerve,and to apply a cathodic current to the vagus nerve which is capable ofinducing action potentials in the vagus nerve; and

an anode, adapted to be disposed at an anodal site of the vagus nerve,and to apply to the vagus nerve an anodal current which is capable ofinhibiting action potentials in the vagus nerve, and

the control unit is adapted to:

drive the cathode to apply to the vagus nerve the cathodic currenthaving a cathodic amplitude sufficient to induce action potentials inthe medium- and large-diameter fibers, but generally insufficient toinduce action potentials in the small-diameter fibers, and

drive the anode to apply to the vagus nerve the anodal current having ananodal amplitude sufficient to inhibit action potentials in thelarge-diameter fibers, but generally insufficient to inhibit actionpotentials in the medium-diameter fibers.

In an embodiment, the control unit is adapted to change the parameterby:

determining a target value of the parameter, which target value issubstantially appropriate for achieving the target heart rate,

determining an intermediate value for the parameter, the intermediatevalue between a current value of the parameter and the target value ofthe parameter, and

setting the parameter at the intermediate value.

In an embodiment, the control unit is adapted to withhold driving theelectrode device upon determining that the heart rate is less than avalue associated with bradycardia.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the current with an amplitude of between about 2 andabout 10 milliamps.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the current in intermittent ones of a plurality ofcardiac cycles of the subject.

In an embodiment, the apparatus includes an electrode selected from thelist consisting of: an electrode for pacing the heart, and an electrodefor defibrillating the heart, and the control unit is adapted towithhold driving the electrode device to apply the current to the vagusnerve when the control unit drives the electrode selected from the list.

In an embodiment, the integral feedback controller is adapted tocalculate a difference between the target heart rate and the detectedheart rate, and the control unit is adapted to set a level of astimulation parameter of the current responsive to a summation over timeof the difference.

In an embodiment, the control unit is adapted to set a level of astimulation parameter of the current by selecting the level from fewerthan 16 discrete values. For some applications, the control unit isadapted to set the level of the stimulation parameter of the current byselecting the level from fewer than 10 discrete values. For someapplications, the level of the stimulation parameter of the currentincludes a number of pulses to apply during a cardiac cycle, and thecontrol unit is adapted to set the number to be a number between 0 and16.

For some applications, when a value of the level of the stimulationparameter suitable to achieve the target heart rate is between two ofthe discrete values, the control unit is adapted to vary the level, inturns, between the two of the discrete values. For some applications,when the suitable value of the level is between the two discrete values,the control unit is adapted to vary the level from a first one of thetwo discrete values, to a second one of the two discrete values, andback to the first one of the two discrete values, in a time periodlasting fewer than 20 heartbeats. For some applications, when thesuitable value of the level is between the two discrete values, thecontrol unit is adapted to vary the level from a first one of the twodiscrete values, to a second one of the two discrete values, and back tothe first one of the two discrete values, in a time period lasting fewerthan 10 heartbeats.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the current in respective pulse bursts in each of aplurality of cardiac cycles of the subject. The at least one parametermay include a number of pulses per burst, and the control unit isadapted to change the at least one parameter by changing the number ofpulses per burst no more than once in any given approximately 15-secondperiod during operation of the apparatus. Alternatively or additionally,the at least one parameter includes a number of pulses per burst, andthe control unit is adapted to change the at least one parameter bychanging, during any given approximately 15-second period duringoperation of the apparatus, the number of pulses per burst by no morethan one pulse.

In an embodiment, the control unit is adapted to configure each pulse ofeach of the bursts to have a pulse duration of between about 0.2 andabout 4 milliseconds. In an embodiment, the control unit is adapted toconfigure each of the bursts to have a pulse repetition interval ofgreater than about 3 milliseconds.

In an embodiment, the control unit is adapted to configure at least oneof the bursts to have between about 0 and about 8 pulses.

In an embodiment, the apparatus includes an electrocardiogram (ECG)monitor, adapted to measure an ECG signal, the control unit is adaptedto receive the ECG signal, and to initiate the applying of each burstafter a delay following detection of a feature of the ECG.

In an embodiment, the control unit is adapted to set a control parameterof a feedback algorithm governing the current application to be a numberof pulses per burst.

In an embodiment, the at least one parameter includes a number of pulsesper burst, and the control unit is adapted to change the at least oneparameter by changing, over the period, the number of pulses per burstby less than about three pulses. For some applications, the control unitis adapted to change the at least one parameter by changing, over theperiod, the number of pulses per burst by exactly one pulse.Alternatively or additionally, the control unit is adapted to change theat least one parameter by changing, during each of two consecutiveperiods, the number of pulses per burst by less than about three pulses,each of the two consecutive periods having a duration of at least about15 seconds. The control unit may be adapted to change the at least oneparameter by changing, during each of the two consecutive periods, thenumber of pulses per burst by exactly one pulse.

In an embodiment, the control unit is adapted to change the at least oneparameter at a rate of change, the rate of change determined at least inpart responsive to a heart rate variable selected from: an R-R intervalof the subject and a time derivative of the heart rate of the subject.For some applications, the control unit is adapted to increase the rateof change as the heart rate approaches a threshold limit greater than anormal heart rate of the subject. For other applications, the controlunit is adapted to increase the rate of change as the heart rateapproaches a threshold limit less than a normal heart rate of thesubject. Alternatively or additionally, the control unit is adapted todecrease the rate of change as the heart rate increases, and to increasethe rate of change as the heart rate decreases.

In an embodiment, the control unit is adapted to use a time derivativeof an R-R interval of the subject as an input to a feedback algorithmgoverning the current application.

In an embodiment, the control unit is adapted to correct for an absenceof an expected heartbeat.

For some applications, the control unit is adapted to sense an R-Rinterval and: (a) store the sensed R-R interval, if the sensed R-Rinterval is less than a threshold value, and (b) store the thresholdvalue, if the sensed R-R interval is greater than the threshold value.

In an embodiment, the control unit is adapted to cycle between “on”periods, during which the control unit drives the electrode device toapply the current, and “off” periods, during which the control unitwithholds driving the electrode device. For some applications, thecontrol unit is adapted to determine a desired level of stimulationapplied by the electrode device, and to configure the cycling betweenthe “on” and “off” periods responsive to the desired level ofstimulation. For some applications, the control unit is adapted to seteach of the “on” periods to have a duration of less than about 300seconds. For some applications, the control unit is adapted to set eachof the “off” periods to have a duration of between about 0 and about 300seconds.

In an embodiment, the control unit is adapted to set the parameter at abeginning of one of the “on”periods equal to a value of the parameter atan end of an immediately preceding one of the “on” periods. In anembodiment, the control unit is adapted to configure the current usingan algorithm that disregards between about one and about five heartbeats at a beginning of each of the “on” periods.

In an embodiment, the control unit is adapted to set the target heartrate during at least one of the “on” periods at least in part responsiveto a historic heart rate sensed during a preceding one of the“off”periods. The control unit may be adapted to set the target heartrate during the at least one of the “on” periods at least in partresponsive to a historic heart rate sensed during an immediatelypreceding one of the “off” periods.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, apparatus for treating a heart condition of asubject, including:

an electrode device, adapted to be coupled to a vagus nerve of thesubject; and

a control unit, adapted to cycle between “on” periods, during which thecontrol unit drives the electrode device to apply a current to the vagusnerve, and “off” periods, during which the control unit withholdsdriving the electrode device, so as to treat the heart condition.

In an embodiment, the control unit is adapted to withhold driving theelectrode device upon determining that the heart rate is less than avalue associated with bradycardia. In an embodiment, the control unit isadapted to drive the electrode device to apply the current with anamplitude of between about 2 and about 10 milliamps. In an embodiment,the control unit is adapted to drive the electrode device to apply thecurrent in intermittent ones of a plurality of cardiac cycles of thesubject.

In an embodiment, the apparatus includes an electrode selected from thelist consisting of: an electrode for pacing the heart, and an electrodefor defibrillating the heart, and the control unit is adapted towithhold driving the electrode device to apply the current to the vagusnerve during an “on” period if the control unit is driving the electrodeselected from the list.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the current in respective pulse bursts in each of aplurality of cardiac cycles of the subject. For some applications, thecontrol unit is adapted to configure each pulse of each of the bursts tohave a pulse duration of between about 0.2 and about 4 milliseconds. Forsome applications, the control unit is adapted to configure each of thebursts to have a pulse repetition interval of greater than about 3milliseconds. For some applications, the control unit is adapted toconfigure at least one of the bursts to have between about 0 and about 8pulses. In an embodiment, the apparatus includes an electrocardiogram(ECG) monitor, adapted to measure an ECG signal, the control unit isadapted to receive the ECG signal, and to initiate the applying of eachburst after a delay following detection of a feature of the ECG.

In an embodiment, the control unit is adapted to configure the currentto include a stimulating current, which is capable of inducing actionpotentials in a first set and a second set of nerve fibers of the vagusnerve, and an inhibiting current, which is capable of inhibiting theinduced action potentials traveling in the second set of nerve fibers,the nerve fibers in the second set having generally larger diametersthan the nerve fibers in the first set, and the control unit is adaptedto drive the electrode device to apply the stimulating current and theinhibiting current to the vagus nerve.

In an embodiment, the current includes a stimulating current, which iscapable of inducing action potentials in the vagus nerve, and aninhibiting current, which is capable of inhibiting device-induced actionpotentials traveling in the vagus nerve in an afferent direction towarda brain of the subject, and the control unit is adapted to drive theelectrode device to apply the stimulating current and the inhibitingcurrent to the vagus nerve.

In an embodiment, the vagus nerve includes small-, medium-, andlarge-diameter fibers, and the electrode device includes:

a cathode, adapted to be disposed at a cathodic site of the vagus nerve,and to apply a cathodic current to the vagus nerve which is capable ofinducing action potentials in the vagus nerve; and

an anode, adapted to be disposed at an anodal site of the vagus nerve,and to apply to the vagus nerve an anodal current which is capable ofinhibiting action potentials in the vagus nerve, and

the control unit is adapted to:

drive the cathode to apply to the vagus nerve the cathodic currenthaving a cathodic amplitude sufficient to induce action potentials inthe medium- and large-diameter fibers, but generally insufficient toinduce action potentials in the small-diameter fibers, and

drive the anode to apply to the vagus nerve the anodal current having ananodal amplitude sufficient to inhibit action potentials in thelarge-diameter fibers, but generally insufficient to inhibit actionpotentials in the medium-diameter fibers.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for treating a subject, including:

an electrode device, adapted to be coupled to a vagus nerve of thesubject;

a sensor, configured to detect a heart rate of the subject, and togenerate a heart rate signal responsive thereto; and

a control unit, adapted to:

receive the heart rate signal,

drive the electrode device to apply a current to the vagus nerve, and

configure the current to increase a variability of the heart rate.

In an embodiment, the control unit is adapted to configure the currentto include a stimulating current, which is capable of inducing actionpotentials in a first set and a second set of nerve fibers of the vagusnerve, and an inhibiting current, which is capable of inhibiting theinduced action potentials traveling in the second set of nerve fibers,the nerve fibers in the second set having generally larger diametersthan the nerve fibers in the first set, and the control unit is adaptedto drive the electrode device to apply the stimulating current and theinhibiting current to the vagus nerve.

In an embodiment, the current includes a stimulating current, which iscapable of inducing action potentials in the vagus nerve, and aninhibiting current, which is capable of inhibiting device-induced actionpotentials traveling in the vagus nerve in an afferent direction towarda brain of the subject, and the control unit is adapted to drive theelectrode device to apply the stimulating current and the inhibitingcurrent to the vagus nerve.

In an embodiment, the vagus nerve includes small-, medium-, andlarge-diameter fibers, and the electrode device includes:

a cathode, adapted to be disposed at a cathodic site of the vagus nerve,and to apply a cathodic current to the vagus nerve which is capable ofinducing action potentials in the vagus nerve; and

an anode, adapted to be disposed at an anodal site of the vagus nerve,and to apply to the vagus nerve an anodal current which is capable ofinhibiting action potentials in the vagus nerve, and

the control unit is adapted to:

drive the cathode to apply to the vagus nerve the cathodic currenthaving a cathodic amplitude sufficient to induce action potentials inthe medium- and large-diameter fibers, but generally insufficient toinduce action potentials in the small-diameter fibers, and

drive the anode to apply to the vagus nerve the anodal current having ananodal amplitude sufficient to inhibit action potentials in thelarge-diameter fibers, but generally insufficient to inhibit actionpotentials in the medium-diameter fibers.

For some applications, the control unit is adapted to configure thecurrent to increase the variability of the heart rate above a targetheart rate variability.

For some applications, the sensor includes an electrocardiogram (ECG)monitor.

For some applications, the control unit is adapted to withhold drivingthe electrode device upon determining that the heart rate is less than avalue associated with bradycardia.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the current with an amplitude of between about 2 andabout 10 milliamps. In an embodiment, the control unit is adapted todrive the electrode device to apply the current in intermittent ones ofa plurality of cardiac cycles of the subject.

In an embodiment, the apparatus includes an electrode selected from thelist consisting of: an electrode for pacing the heart, and an electrodefor defibrillating the heart, and the control unit is adapted towithhold driving the electrode device to apply the current to the vagusnerve if the control unit is driving the electrode selected from thelist.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the current in respective pulse bursts in each of aplurality of cardiac cycles of the subject. For some applications, thecontrol unit is adapted to configure each pulse of each of the bursts tohave a pulse duration of between about 0.2 and about 4 milliseconds. Forsome applications, the control unit is adapted to configure each of thebursts to have a pulse repetition interval of greater than about 3milliseconds. For some applications, the control unit is adapted toconfigure at least one of the bursts to have between about 0 and about 8pulses. In an embodiment, the apparatus includes an electrocardiogram(ECG) monitor, adapted to measure an ECG signal, the control unit isadapted to receive the ECG signal, and to initiate the applying of eachburst after a delay following detection of a feature of the ECG.

In an embodiment, the control unit is adapted to configure the currentusing a feedback algorithm.

There is further provided, in accordance with an embodiment of thepresent invention, a method for treating a subject, including:

detecting a heart rate of the subject; and

responsive to determining that the heart rate is greater than athreshold value, which threshold value is greater than a normal heartrate, applying a current to a vagus nerve of the subject, andconfiguring the current so as to reduce the heart rate of the subject.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for applying current to a vagus nerve,including:

applying to the vagus nerve, through a common conductor, an anodalcurrent at a first anodal site of the vagus nerve and at a second anodalsite of the vagus nerve; and

applying a cathodic current to the vagus nerve at a cathodic site of thevagus nerve, so as to stimulate the vagus nerve, the cathodic sitedisposed between the first anodal site and the second anodal site.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method for treating a subject, including:

detecting a heart rate of the subject;

applying a current to a vagus nerve of the subject; and

configuring the current so as to reduce the heart rate toward a targetheart rate, responsive to an output of an integral feedback controllerwhose inputs include the detected heart rate and a target heart rate.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method for treating a heart condition of asubject, including:

cycling between “on” and “off” periods;

during the “on” periods, applying a current to a vagus nerve of thesubject; and

during the “off” periods, withholding applying the current, so as totreat the heart condition.

There is also provided, in accordance with an embodiment of the presentinvention, a method for treating a subject, including:

detecting a heart rate of the subject;

applying a current to a vagus nerve of the subject; and

configuring the current to increase a variability of the heart rate.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for treating a subject suffering from aheart condition, including:

an electrode device, adapted to be coupled to a vagus nerve of thesubject; and

a control unit, adapted to drive the electrode device to apply a currentto the vagus nerve, and to configure the current to suppress anadrenergic system of the subject, so as to treat the subject.

In an embodiment, the heart condition includes heart failure, and thecontrol unit is adapted to configure the current to treat the heartfailure.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus for treating a subject suffering from aheart condition, including:

an electrode device, adapted to be coupled to a vagus nerve of thesubject; and

a control unit, adapted to drive the electrode device to apply a currentto the vagus nerve, and to configure the current to modulatecontractility of at least a portion of a heart of the subject, so as totreat the subject.

In an embodiment, the control unit is adapted to configure the currentto reduce atrial and ventricular contractility.

In an embodiment, the heart condition includes hypertrophic cardiopathy,and the control unit is adapted to configure the current so as to treatthe hypertrophic cardiopathy.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus for treating a subject suffering from aheart condition, including:

an electrode device, adapted to be coupled to a vagus nerve of thesubject; and

a control unit, adapted to drive the electrode device to apply a currentto the vagus nerve, and to configure the current to increase coronaryblood flow, so as to treat the subject.

In an embodiment, the heart condition is selected from the listconsisting of: myocardial ischemia, ischemic heart disease, heartfailure, and variant angina, and the control unit is adapted toconfigure the current to increase the coronary blood flow so as to treatthe selected heart condition.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a treatment method, including:

identifying a subject suffering from a heart condition;

applying a current to a vagus nerve of the subject; and

configuring the current to suppress an adrenergic system of the subject,so as to treat the subject.

There is also provided, in accordance with an embodiment of the presentinvention, a treatment method, including:

identifying a subject suffering from a heart condition;

applying a current to a vagus nerve of the subject; and

configuring the current to modulate contractility of at least a portionof a heart of the subject, so as to treat the subject.

There is further provided, in accordance with an embodiment of thepresent invention, a treatment method, including:

identifying a subject suffering from a heart condition;

applying a current to a vagus nerve of the subject; and

configuring the current to increase coronary blood flow, so as to treatthe subject.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus including:

an electrode device, adapted to be coupled to a vagus nerve of asubject; and

a control unit, adapted to drive the electrode device to apply to thevagus nerve a current that reduces heart rate variability of thesubject.

In an embodiment, the control unit is adapted to configure the currentto substantially not reduce a heart rate of the subject.

In an embodiment, the control unit is adapted to configure the currentto reduce the heart rate variability by at least 5% below a baselinethereof during a time period in which a heart rate of the subject is notreduced responsive to the current by more than 10% below a baselinethereof.

In an embodiment, the control unit is adapted to configure the currentto effect a reduction of a heart rate of the subject while reducing theheart rate variability of the subject.

For some applications, the control unit is adapted to drive theelectrode device during exertion by the subject. Alternatively, thecontrol unit is adapted to withhold driving the electrode device whenthe subject is not experiencing exertion.

For some applications, the control unit is adapted to configure thecurrent to reduce a heart rate variability of the subject having acharacteristic frequency between about 0.15 and about 0.4 Hz.Alternatively or additionally, the control unit is adapted to configurethe current to reduce a heart rate variability of the subject having acharacteristic frequency between about 0.04 and about 0.15 Hz.

For some applications, the control unit is adapted to drive theelectrode device to apply the current with an amplitude of between about2 and about 10 milliamps.

For some applications, the control unit is adapted to drive theelectrode device to apply the current in intermittent ones of aplurality of cardiac cycles of the subject. For some applications, thecontrol unit is adapted to drive the electrode device to apply thecurrent unsynchronized with a cardiac cycle of the subject.

In an embodiment, the control unit is adapted to drive the electrodedevice responsive to a circadian rhythm of the subject. For someapplications, the control unit is adapted to drive the electrode devicewhen the subject is awake. For some applications, the control unit isadapted to withhold driving the electrode device when the subject issleeping.

For some applications, the control unit is adapted to drive theelectrode device to apply the current in a manner that reduces the heartrate variability by at least 10%. For some applications, the controlunit is adapted to drive the electrode device to apply the current in amanner that reduces the heart rate variability by at least 50%.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the current in a manner that reduces a standarddeviation of a heart rate of the subject within a time window, e.g., atime window that is longer than 10 seconds. For some applications, thestandard deviation of the heart rate is reduced by at least about 10% orat least about 50% within the time window that is longer than 10seconds.

In an embodiment, the control unit is adapted to drive the electrodedevice to apply the current in respective pulse bursts in each of aplurality of cardiac cycles of the subject.

For some applications, the control unit is adapted to configure eachpulse of each of the bursts to have a pulse duration of between about0.1 and about 4 milliseconds. For some applications, the control unit isadapted to configure each pulse of each of the bursts to have a pulseduration of between about 0.5 and about 2 milliseconds. For someapplications, the control unit is adapted to configure each of thebursts to have a pulse repetition interval of between about 2 and about10 milliseconds. For some applications, the control unit is adapted toconfigure each of the bursts to have a pulse repetition interval ofbetween about 2 and about 6 milliseconds.

In an embodiment, the apparatus includes a cardiac monitor, adapted togenerate a cardiac signal, and the control unit is adapted to receivethe cardiac signal, and to initiate the applying of each burst after adelay following detection of a feature of the cardiac signal. For someapplications, the control unit is adapted to initiate the applying ofeach burst after a delay of about 30 to about 200 milliseconds followingan R-wave of the cardiac signal. For some applications, the control unitis adapted to initiate the applying of each burst after a delay of about50 to about 150 milliseconds following an R-wave of the cardiac signal.

For some applications, the control unit is adapted to configure at leastone of the bursts to have between about 0 and about 20 pulses. For someapplications, the control unit is adapted to configure the bursts tohave between about 1 and about 8 pulses during steady state operation.

In an embodiment, the apparatus includes a heart sensor, configured todetect heart activity of the subject, and to generate a heart signalresponsive thereto, and the control unit is adapted to receive the heartsignal, and, responsive to receiving the heart signal, drive theelectrode device to apply the current to the vagus nerve.

For some applications, the control unit is adapted to, responsive toreceiving the heart signal, drive the electrode device to apply to thevagus nerve the current synchronized with a cardiac cycle of thesubject. For some applications, the control unit is adapted to,responsive to receiving the heart signal, drive the electrode device toapply to the vagus nerve the current unsynchronized with a cardiac cycleof the subject.

In an embodiment, the control unit is adapted to configure the currentto reduce a heart rate of the subject.

In an embodiment, the apparatus includes a sensor, configured to detectthe heart rate of the subject, and to generate a heart rate signalresponsive thereto, and the control unit includes an integral feedbackcontroller that has inputs including the detected heart rate and atarget heart rate, and the control unit is adapted to configure thecurrent responsive to an output of the integral feedback controller, soas to reduce the heart rate of the subject toward the target heart rate.For some applications, the target heart rate includes a target normalheart rate within a range of normal heart rates of the subject, and thecontrol unit is adapted to configure the current so as to reduce theheart rate of the subject toward the target normal heart rate.

In an embodiment, the control unit is adapted to configure the currentto reduce the heart rate variability so as to treat a condition of thesubject. For some applications, the condition includes heart failure ofthe subject, and the control unit is adapted to configure the current toreduce the heart rate variability by at least about 10% so as to treatthe heart failure. For some applications, the condition includes anoccurrence of arrhythmia of the subject, and the control unit is adaptedto configure the current to reduce the heart rate variability by atleast about 10% so as to treat the occurrence of arrhythmia. For someapplications, the condition includes atrial fibrillation of the subject,and the control unit is adapted to configure the current to reduce theheart rate variability so as to treat the atrial fibrillation.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method including applying to a vagus nerve of asubject a current that reduces heart rate variability of the subject.

The present invention will be more fully understood from the followingdetailed description of an embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram that schematically illustrates a vagalstimulation system applied to a vagus nerve of a patient, in accordancewith an embodiment of the present invention;

FIG. 2A is a simplified cross-sectional illustration of a multipolarelectrode device applied to a vagus nerve, in accordance with anembodiment of the present invention;

FIG. 2B is a simplified cross-sectional illustration of agenerally-cylindrical electrode device applied to a vagus nerve, inaccordance with an embodiment of the present invention;

FIG. 2C is a simplified perspective illustration of the electrode deviceof FIG. 2A, in accordance with an embodiment of the present invention;

FIG. 3 is a simplified perspective illustration of a multipolar pointelectrode device applied to a vagus nerve, in accordance with anembodiment of the present invention;

FIG. 4 is a conceptual illustration of the application of current to avagus nerve, in accordance with an embodiment of the present invention;

FIG. 5 is a simplified illustration of an electrocardiogram (ECG)recording and of example timelines showing the timing of the applicationof a series of stimulation pulses, in accordance with an embodiment ofthe present invention; and

FIG. 6 is a graph showing in vivo experimental results, measured inaccordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF EMBODIMENTS

FIG. 1 is a block diagram that schematically illustrates a vagalstimulation system 18 comprising a multipolar electrode device 40, inaccordance with an embodiment of the present invention. Electrode device40 is applied to a portion of a vagus nerve 36 (either a left vagusnerve 37 or a right vagus nerve 39), which innervates a heart 30 of apatient 31. Typically, system 18 is utilized for treating a heartcondition such as heart failure and/or cardiac arrhythmia. Vagalstimulation system 18 further comprises an implanted or external controlunit 20, which typically communicates with electrode device 40 over aset of leads 42. Control unit 20 drives electrode device 40 to (i) applysignals to induce the propagation of efferent nerve impulses towardsheart 30, and (ii) suppress artificially-induced afferent nerve impulsestowards a brain 34 of the patient, in order to minimize unintended sideeffects of the signal application. The efferent nerve pulses in vagusnerve 36 are induced by electrode device 40 in order to regulate theheart rate of the patient.

For some applications, control unit 20 is adapted to receive feedbackfrom one or more of the electrodes in electrode device 40, and toregulate the signals applied to the electrode device responsive thereto.

Control unit 20 is typically adapted to receive and analyze one or moresensed physiological parameters or other parameters of the patient, suchas heart rate, electrocardiogram (ECG), blood pressure, indicators ofdecreased cardiac contractility, cardiac output, norepinephrineconcentration, or motion of the patient. In order to receive thesesensed parameters, control unit 20 may comprise, for example, an ECGmonitor 24, connected to a site on the patient's body such as heart 30,for example using one or more subcutaneous sensors or ventricular and/oratrial intracardiac sensors. The control unit may also comprise anaccelerometer 22 for detecting motion of the patient. Alternatively, ECGmonitor 24 and/or accelerometer 22 comprise separate implanted devicesplaced external to control unit 20, and, optionally, external to thepatient's body. Alternatively or additionally, control unit 20 receivessignals from one or more physiological sensors 26, such as bloodpressure sensors. Sensors 26 are typically implanted in the patient, forexample in a left ventricle 32 of heart 30. In an embodiment, controlunit 20 comprises or is coupled to an implanted device 25 for monitoringand correcting the heart rate, such as an implantable cardioverterdefibrillator (ICD) or a pacemaker (e.g., a bi-ventricular or standardpacemaker). For example, implanted device 25 may be incorporated into acontrol loop executed by control unit 20, in order to increase the heartrate when the heart rate for any reason is too low.

FIG. 2A is a simplified cross-sectional illustration of agenerally-cylindrical electrode device 40 applied to vagus nerve 36, inaccordance with an embodiment of the present invention. Electrode device40 comprises a central cathode 46 for applying a negative current(“cathodic current”) in order to stimulate vagus nerve 36, as describedbelow. Electrode device 40 additionally comprises a set of one or moreanodes 44 (44 a, 44 b, herein: “efferent anode set 44”), placed betweencathode 46 and the edge of electrode device 40 closer to heart 30 (the“efferent edge”) Efferent anode set 44 applies a positive current(“efferent anodal current”) to vagus nerve 36, for blocking actionpotential conduction in vagus nerve 36 induced by the cathodic current,as described below. Typically, electrode device 40 comprises anadditional set of one or more anodes 45 (45 a, 45 b, herein: “afferentanode set 45”), placed between cathode 46 and the edge of electrodedevice 40 closer to brain 34. Afferent anode set 45 applies a positivecurrent (“afferent anodal current”) to vagus nerve 36, in order to blockpropagation of action potentials in the direction of the brain duringapplication of the cathodic current.

For some applications, the one or more anodes of efferent anode set 44are directly electrically coupled to the one or more anodes of afferentanode set 45, such as by a common wire or shorted wires providingcurrent to both anode sets substantially without any intermediaryelements. Typically, coatings on the anodes, shapes of the anodes,positions of the anodes, sizes of the anodes and/or distances of thevarious anodes from the nerve are regulated so as to produce desiredratios of currents and/or desired activation functions delivered throughor caused by the various anodes. For example, by varying one or more ofthese characteristics, the relative impedance between the respectiveanodes and central cathode 46 is regulated, whereupon more anodalcurrent is driven through the one or more anodes having lower relativeimpedance. In these applications, central cathode 46 is typically placedcloser to one of the anode sets than to the other, for example, so as toinduce asymmetric stimulation (i.e., not necessarily unidirectional inall fibers) between the two sides of the electrode device. The closeranode set typically induces a stronger blockade of the cathodicstimulation.

Reference is now made to FIG. 2B, which is a simplified cross-sectionalillustration of a generally-cylindrical electrode device 240 applied tovagus nerve 36, in accordance with an embodiment of the presentinvention. Electrode device 240 comprises exactly one efferent anode 244and exactly one afferent anode 245, which are electrically coupled toeach other, such as by a common wire 250 or shorted wires providingcurrent to both anodes 244 and 245, substantially without anyintermediary elements. The cathodic current is applied by a cathode 246with an amplitude sufficient to induce action potentials in large- andmedium-diameter fibers (e.g., A- and B-fibers), but insufficient toinduce action potentials in small-diameter fibers (e.g., C-fibers).

Reference is again made to FIG. 2A. Cathodes 46 and anode sets 44 and 45(collectively, “electrodes”) are typically mounted in anelectrically-insulating cuff 48 and separated from one another byinsulating elements such as protrusions 49 of the cuff. Typically, thewidth of the electrodes is between about 0.5 and about 2 millimeters, oris equal to approximately one-half the radius of the vagus nerve. Theelectrodes are typically recessed so as not to come in direct contactwith vagus nerve 36. For some applications, such recessing enables theelectrodes to achieve generally uniform field distributions of thegenerated currents and/or generally uniform values of the activationfunction defined by the electric potential field in the vicinity ofvagus nerve 24. Alternatively or additionally, protrusions 49 allowvagus nerve 24 to swell into the canals defined by the protrusions,while still holding the vagus nerve centered within cuff 48 andmaintaining a rigid electrode geometry. For some applications, cuff 48comprises additional recesses separated by protrusions, which recessesdo not contain active electrodes. Such additional recesses accommodateswelling of vagus nerve 24 without increasing the contact area betweenthe vagus nerve and the electrodes. For some applications, the distancebetween the electrodes and the axis of the vagus nerve is between about1 and about 4 millimeters, and is greater than the closest distance fromthe ends of the protrusions to the axis of the vagus nerve. Typically,protrusions 49 are relatively short (as shown). For some applications,the distance between the ends of protrusions 49 and the center of thevagus nerve is between about 1 and 3 millimeters. (Generally, thediameter of the vagus nerve is between about 2 and 3 millimeters.)Alternatively, for some applications, protrusions 49 are longer and/orthe electrodes are placed closer to the vagus nerve in order to reducethe energy consumption of electrode device 40.

In an embodiment of the present invention, efferent anode set 44comprises a plurality of anodes 44, typically two anodes 44 a and 44 b,spaced approximately 0.5 to 2.0 millimeters apart. Application of theefferent anodal current in appropriate ratios from a plurality of anodesgenerally minimizes the “virtual cathode effect,” whereby application oftoo large an anodal current stimulates rather than blocks fibers. In anembodiment, anode 44 a applies a current with an amplitude equal toabout 0.5 to about 5 milliamps (typically one-third of the amplitude ofthe current applied by anode 44 b). When such techniques are not used,the virtual cathode effect generally hinders blocking ofsmaller-diameter fibers, as described below, because a relatively largeanodal current is generally necessary to block such fibers.

Anode 44 a is typically positioned in cuff 48 to apply current at thelocation on vagus nerve 36 where the virtual cathode effect is maximallygenerated by anode 44 b. For applications in which the blocking currentthrough anode 44 b is expected to vary substantially, efferent anode set44 typically comprises a plurality of virtual-cathode-inhibiting anodes44 a, one or more of which is activated at any time based on theexpected magnitude and location of the virtual cathode effect.

Likewise, afferent anode set 45 typically comprises a plurality ofanodes 45, typically two anodes 45 a and 45 b, in order to minimize thevirtual cathode effect in the direction of the brain. In certainelectrode configurations, cathode 46 comprises a plurality of cathodesin order to minimize the “virtual anode effect,” which is analogous tothe virtual cathode effect.

As appropriate, techniques described herein are practiced in conjunctionwith methods and apparatus described in U.S. patent application Ser. No.10/205,474 to Gross et al., filed Jul. 24, 2002, entitled, “Electrodeassembly for nerve control,” which published as U.S. Patent Publication2003/0050677, is assigned to the assignee of the present patentapplication, and is incorporated herein by reference. Alternatively oradditionally, techniques described herein are practiced in conjunctionwith methods and apparatus described in U.S. patent application Ser. No.10/205,475 to Gross et al., filed Jul. 24, 2002, entitled, “Selectivenerve fiber stimulation for treating heart conditions,” which publishedas U.S. Patent Publication 2003/0045909, is assigned to the assignee ofthe present patent application, and is incorporated herein by reference.Further alternatively or additionally, techniques described herein arepracticed in conjunction with methods and apparatus described in U.S.Provisional Patent Application 60/383,157 to Ayal et al., filed May 23,2002, entitled, “Inverse recruitment for autonomic nerve systems,” whichis assigned to the assignee of the present patent application and isincorporated herein by reference.

FIG. 2C is a simplified perspective illustration of electrode device 40(FIG. 2A), in accordance with an embodiment of the present invention.When applied to vagus nerve 36, electrode device 40 typicallyencompasses the nerve. As described, control unit 20 typically driveselectrode device 40 to (i) apply signals to vagus nerve 36 in order toinduce the propagation of efferent action potentials towards heart 30,and (ii) suppress artificially-induced afferent action potentialstowards brain 34. The electrodes typically comprise ring electrodesadapted to apply a generally uniform current around the circumference ofthe nerve, as best shown in FIG. 2C.

FIG. 3 is a simplified perspective illustration of a multipolar pointelectrode device 140 applied to vagus nerve 36, in accordance with anembodiment of the present invention. In this embodiment, anodes 144 aand 144 b and a cathode 146 typically comprise point electrodes(typically 2 to 100), fixed inside an insulating cuff 148 and arrangedaround vagus nerve 36 so as to selectively stimulate nerve fibersaccording to their positions inside the nerve. In this case, techniquesdescribed in the above-cited articles by Grill et al., Goodall et al.,and/or Veraart et al. are typically used. The point electrodes typicallyhave a surface area between about 0.01 mm² and 1 mm². In someapplications, the point electrodes are in contact with vagus nerve 36,as shown, while in other applications the point electrodes are recessedin cuff 148, so as not to come in direct contact with vagus nerve 36,similar to the recessed ring electrode arrangement described above withreference to FIG. 2A. For some applications, one or more of theelectrodes, such as cathode 146 or anode 144 a, comprise a ringelectrode, as described with reference to FIG. 2C, such that electrodedevice 140 comprises both ring electrode(s) and point electrodes(configuration not shown). Additionally, electrode device 40 optionallycomprises an afferent anode set (positioned like anodes 45 a and 45 b inFIG. 2A), the anodes of which comprise point electrodes and/or ringelectrodes.

Alternatively, ordinary, non-cuff electrodes are used, such as when theelectrodes are placed on the epicardial fat pads instead of on the vagusnerve.

FIG. 4 is a conceptual illustration of the application of current tovagus nerve 36 in order to achieve smaller-to-larger diameter fiberrecruitment, in accordance with an embodiment of the present invention.When inducing efferent action potentials towards heart 30, control unit20 drives electrode device 40 to selectively recruit nerve fibersbeginning with smaller-diameter fibers and to progressively recruitlarger-diameter fibers as the desired stimulation level increases. Thissmaller-to-larger diameter recruitment order mimics the body's naturalorder of recruitment.

Typically, in order to achieve this recruitment order, the control unitstimulates myelinated fibers essentially of all diameters using cathodiccurrent from cathode 46, while simultaneously inhibiting fibers in alarger-to-smaller diameter order using efferent anodal current fromefferent anode set 44. For example, FIG. 4 illustrates the recruitmentof a single, smallest nerve fiber 56, without the recruitment of anylarger fibers 50, 52 and 54. The depolarizations generated by cathode 46stimulate all of the nerve fibers shown, producing action potentials inboth directions along all the nerve fibers. Efferent anode set 44generates a hyperpolarization effect sufficiently strong to block onlythe three largest nerve fibers 50, 52 and 54, but not fiber 56. Thisblocking order of larger-to-smaller diameter fibers is achieved becauselarger nerve fibers are inhibited by weaker anodal currents than aresmaller nerve fibers. Stronger anodal currents inhibit progressivelysmaller nerve fibers. When the action potentials induced by cathode 46in larger fibers 50, 52 and 54 reach the hyperpolarized region in thelarger fibers adjacent to efferent anode set 44, these action potentialsare blocked. On the other hand, the action potentials induced by cathode46 in smallest fiber 56 are not blocked, and continue travelingunimpeded toward heart 30. Anode pole 44 a is shown generating lesscurrent than anode pole 44 b in order to minimize the virtual cathodeeffect in the direction of the heart, as described above.

When desired, in order to increase the parasympathetic stimulationdelivered to the heart, the number of fibers not blocked isprogressively increased by decreasing the amplitude of the currentapplied by efferent anode set 44. The action potentials induced bycathode 46 in the fibers now not blocked travel unimpeded towards theheart. As a result, the parasympathetic stimulation delivered to theheart is progressively increased in a smaller-to-larger diameter fiberorder, mimicking the body's natural method of increasing stimulation.Alternatively or additionally, in order to increase the number of fibersstimulated, while simultaneously decreasing the average diameter offibers stimulated, the amplitudes of the currents applied by cathode 46and efferent anode set 44 are both increased (thereby increasing boththe number of fibers stimulated and blocked). In addition, for any givennumber of fibers stimulated (and not blocked), the amount of stimulationdelivered to the heart can be increased by increasing the PPT,frequency, and/or pulse width of the current applied to vagus nerve 36.

In order to suppress artificially-induced afferent action potentialsfrom traveling towards the brain in response to the cathodicstimulation, control unit 20 typically drives electrode device 40 toinhibit fibers 50, 52, 54 and 56 using afferent anodal current fromafferent anode set 45. When the afferent-directed action potentialsinduced by cathode 46 in all of the fibers reach the hyperpolarizedregion in all of the fibers adjacent to afferent anode set 45, theaction potentials are blocked. Blocking these afferent action potentialsgenerally minimizes any unintended side effects, such as undesired orcounterproductive feedback to the brain, that might be caused by theseaction potentials. Anode 45 b is shown generating less current thananode 45 a in order to minimize the virtual cathode effect in thedirection of the brain, as described above.

In an embodiment of the present invention, the amplitude of the cathodiccurrent applied in the vicinity of the vagus nerve is between about 2milliamps and about 10 milliamps. Such a current is typically used inembodiments that employ techniques for achieving generally uniformstimulation of the vagus nerve, i.e., stimulation in which thestimulation applied to fibers on or near the surface of the vagus nerveis generally no more than about 400% greater than stimulation applied tofibers situated more deeply in the nerve. This corresponds tostimulation in which the value of the activation function at fibers onor near the surface of the vagus nerve is generally no more than aboutfour times greater than the value of the activation function at fiberssituated more deeply in the nerve. For example, as described hereinabovewith reference to FIG. 2A, the electrodes may be recessed so as not tocome in direct contact with vagus nerve 24, in order to achievegenerally uniform values of the activation function. Typically, but notnecessarily, embodiments using approximately 5 mA of cathodic currenthave the various electrodes disposed approximately 0.5 to 2.5 mm fromthe axis of the vagus nerve. Alternatively, larger cathodic currents(e.g., 10-30 mA) are used in combination with electrode distances fromthe axis of the vagus nerve of greater than 2.5 mm (e.g., 2.5-4.0 mm),so as to achieve an even greater level of uniformity of stimulation offibers in the vagus nerve.

In an embodiment of the present invention, the cathodic current isapplied by cathode 46 with an amplitude sufficient to induce actionpotentials in large- and medium-diameter fibers 50, 52, and 54 (e.g., A-and B-fibers), but insufficient to induce action potentials insmall-diameter fibers 56 (e.g., C-fibers). Simultaneously, an anodalcurrent is applied by anode 44 b in order to inhibit action potentialsinduced by the cathodic current in the large-diameter fibers (e.g.,A-fibers). This combination of cathodic and anodal current generallyresults in the stimulation of medium-diameter fibers (e.g., B-fibers)only. At the same time, a portion of the afferent action potentialsinduced by the cathodic current are blocked by anode 45 a, as describedabove. Alternatively, the afferent anodal current is configured to notfully block afferent action potentials, or is simply not applied. Inthese cases, artificial afferent action potentials are neverthelessgenerally not generated in C-fibers, because the applied cathodiccurrent is not strong enough to generate action potentials in thesefibers.

These techniques for efferent stimulation of only B-fibers are typicallyused in combination with techniques described hereinabove for achievinggenerally uniform stimulation of the vagus nerve. Such generally uniformstimulation enables the use of a cathodic current sufficiently weak toavoid stimulation of C-fibers near the surface of the nerve, while stillsufficiently strong to stimulate B-fibers, including B-fibers situatedmore deeply in the nerve, i.e., near the center of the nerve. For someapplications, when employing such techniques for achieving generallyuniform stimulation of the vagus nerve, the amplitude of the cathodiccurrent applied by cathode 46 may be between about 3 and about 10milliamps, and the amplitude of the anodal current applied by anode 44 bmay be between about 1 and about 7 milliamps. (Current applied at adifferent site and/or a different time is used to achieve a net currentinjection of zero.)

In an embodiment of the present invention, stimulation of the vagusnerve is applied responsive to one or more sensed parameters. Controlunit 20 is typically configured to commence or halt stimulation, or tovary the amount and/or timing of stimulation in order to achieve adesired target heart rate, typically based on configuration values andon parameters including one or more of the following:

-   -   Heart rate—the control unit can be configured to drive electrode        device 40 to stimulate the vagus nerve only when the heart rate        exceeds a certain value.    -   ECG readings—the control unit can be configured to drive        electrode device 40 to stimulate the vagus nerve based on        certain ECG readings, such as readings indicative of designated        forms of arrhythmia. Additionally, ECG readings are typically        used for achieving a desire heart rate, as described below with        reference to FIG. 5.    -   Blood pressure—the control unit can be configured to regulate        the current applied by electrode device 40 to the vagus nerve        when blood pressure exceeds a certain threshold or falls below a        certain threshold.    -   Indicators of decreased cardiac contractility—these indicators        include left ventricular pressure (LVP). When LVP and/or        d(LVP)/dt exceeds a certain threshold or falls below a certain        threshold, control unit 20 can drive electrode device 40 to        regulate the current applied by electrode device 40 to the vagus        nerve.    -   Motion of the patient—the control unit can be configured to        interpret motion of the patient as an indicator of increased        exertion by the patient, and appropriately reduce        parasympathetic stimulation of the heart in order to allow the        heart to naturally increase its rate.    -   Heart rate variability—the control unit can be configured to        drive electrode device 40 to stimulate the vagus nerve based on        heart rate variability, which is typically calculated based on        certain ECG readings.    -   Norepinephrine concentration—the control unit can be configured        to drive electrode device 40 to stimulate the vagus nerve based        on norepinephrine concentration.    -   Cardiac output—the control unit can be configured to drive        electrode device 40 to stimulate the vagus nerve based on        cardiac output, which is typically determined using impedance        cardiography.    -   Baroreflex sensitivity—the control unit can be configured to        drive electrode device 40 to stimulate the vagus nerve based on        baroreflex sensitivity.

The parameters and behaviors included in this list are for illustrativepurposes only, and other possible parameters and/or behaviors willreadily present themselves to those skilled in the art, having read thedisclosure of the present patent application.

In an embodiment of the present invention, control unit 20 is configuredto drive electrode device 40 to stimulate the vagus nerve so as toreduce the heart rate of the subject towards a target heart rate. Thetarget heart rate is typically (a) programmable or configurable, (b)determined responsive to one or more sensed physiological values, suchas those described hereinabove (e.g., motion, blood pressure, etc.),and/or (c) determined responsive to a time of day or circadian cycle ofthe subject. Parameters of stimulation are varied in real time in orderto vary the heart-rate-lowering effects of the stimulation. For example,such parameters may include the amplitude of the applied current.Alternatively or additionally, in an embodiment of the presentinvention, the stimulation is applied in a series of pulses that aresynchronized or are not synchronized with the cardiac cycle of thesubject, such as described hereinbelow with reference to FIG. 5.Parameters of such pulse series typically include, but are not limitedto:

-   -   Timing of the stimulation within the cardiac cycle. Delivery of        the series of pulses typically begins after a fixed or variable        delay following an ECG feature, such as each R- or P-wave. For        some applications, the delay is between about 20 ms and about        300 ms from the R-wave, or between about 100 and about 500 ms        from the P-wave.    -   Pulse duration (width). Longer pulse durations typically result        in a greater heart-rate-lowering effect. For some applications,        the pulse duration is between about 0.2 and about 4 ms.    -   Pulse repetition interval. Maintaining a pulse repetition        interval (the time from the initiation of a pulse to the        initiation of the following pulse) greater than about 3 ms        generally results in maximal stimulation effectiveness for        multiple pulses within a burst.    -   Pulses per trigger (PPT). A greater PPT (the number of pulses in        each series of pulses after a trigger such as an R-wave)        typically results in a greater heart-rate-lowering effect. For        some applications, PPT is between about 0 and about 8.    -   Amplitude. A greater amplitude of the signal applied typically        results in a greater heart-rate-lowering effect. The amplitude        is typically less than about 10 milliamps, e.g., between about 2        and about 10 milliamps. For some applications, the amplitude is        between about 2 and about 6 milliamps.    -   Duty cycle. Application of stimulation every heartbeat typically        results in a greater heart-rate-lowering effect. For less heart        rate reduction, stimulation is applied only once every several        heartbeats.    -   Choice of vagus nerve. Stimulation of the right vagus nerve        typically results in greater heart rate reduction than        stimulation of the left vagus nerve.    -   “On”/“off” ratio and timing. For some applications, the device        operates intermittently, alternating between “on” and “off”        states, the length of each state typically between 0 and about        300 seconds (with a 0-length “off” state equivalent to always        “on”). Greater heart rate reduction is typically achieved if the        device is “on” a greater portion of the time.

For some applications, values of the “on”/“off” parameter are determinedin real time, responsive to one or more inputs, such as sensedphysiological values. Such inputs typically include motion or activityof the subject (e.g., detected using an accelerometer), the averageheart rate of the subject when the device is in “off” mode, and/or thetime of day. For example, the device may operate in continuous “on” modewhen the subject is exercising and therefore has a high heart rate, andthe device may alternate between “on” and “off” when the subject is atrest. As a result, the heart-rate-lowering effect is concentrated duringperiods of high heart rate, and the nerve is allowed to rest when theheart rate is generally naturally lower.

For some applications, heart rate regulation is achieved by setting twoor more parameters in combination. For example, if it is desired toapply 5.2 pulses of stimulation, the control unit may apply 5 pulses of1 ms duration each, followed by a single pulse of 0.2 ms duration. Forother applications, the control unit switches between two values of PPT,so that the desired PPT is achieved by averaging the applied PPTs. Forexample, a sequence of PPTs may be 5, 5, 5, 5, 6, 5, 5, 5, 5, 6, . . . ,in order to achieve an effective PPT of 5.2.

In an embodiment of the present invention, control unit 20 uses aslow-reacting heart rate regulation algorithm to modifyheart-rate-controlling parameters of the stimulation, i.e., thealgorithm varies stimulation parameters slowly in reaction to changes inheart rate. For example, in response to a sudden increase in heart rate,e.g., an increase from a target heart rate of 60 beats per minute (BPM)to 100 BPM over a period of only a few seconds, the algorithm slowlyincreases the stimulation level over a period of minutes. If the heartrate naturally returns to the target rate over this period, thestimulation levels generally do not change substantially beforereturning to baseline levels.

For example, the heart of a subject is regulated while the subject isinactive, such as while sitting. When the subject suddenly increases hisactivity level, such as by standing up or climbing stairs, the subject'sheart rate increases suddenly. In response, the control unit adjusts thestimulation parameters slowly to reduce the subject's heart rate. Such agradual modification of stimulation parameters allows the subject toengage in relatively stressful activities for a short period of timebefore his heart rate is substantially regulated, generally resulting inan improved quality of life.

In an embodiment of the present invention, control unit 20 is adapted todetect bradycardia (i.e., that an average detected R-R interval exceedsa preset bradycardia limit), and to terminate heart rate regulationsubstantially immediately upon such detection, such as by ceasing vagalstimulation. Alternatively or additionally, the control unit uses analgorithm that reacts quickly to regulate heart rate when the heart ratecrosses limits that are predefined (e.g., a low limit of 40 beats perminute (BPM) and a high limit of 140 BPM), or determined in real time,such as responsive to sensed physiological values.

In an embodiment of the present invention, control unit 20 is configuredto operate intermittently. Typically, upon each resumption of operation,control unit 20 sets the stimulation parameters to those in effectimmediately prior to the most recent cessation of operation. For someapplications, such parameters applied upon resumption of operation aremaintained without adjustment for a certain number of heartbeats (e.g.,between about one and about ten), in order to allow the heart rate tostabilize after resumption of operation.

For some applications, control unit 20 is configured to operateintermittently with gradual changes in stimulation. For example, thecontrol unit may operate according to the following “on”/“off” pattern:(a) “off” mode for 30 minutes, (b) a two-minute “on” periodcharacterized by a gradual increase in stimulation so as to achieve atarget heart rate, (c) a six-minute “on” period of feedback-controlledstimulation to maintain the target heart rate, and (d) a two-minute “on”period characterized by a gradual decrease in stimulation to return theheart rate to baseline. The control unit then repeats the cycle,beginning with another 30-minute “off” period.

In an embodiment of the present invention, control unit 20 is configuredto operate in an adaptive intermittent mode. The control unit sets thetarget heart rate for the “on” period equal to a fixed or configurablefraction of the average heart rate during the previous “off” period,typically bounded by a preset minimum. For example, assume that for acertain subject the average heart rates during sleep and during exerciseare 70 and 150 BPM, respectively. Further assume that the target heartrate for the “on” period is set at 70% of the average heart rate duringthe previous “off” period, with a minimum of 60 BPM. During sleep,stimulation is applied so as to produce a heart rate of MAX(60 BPM, 70%of 70 BPM)=60 BPM, and is thus applied with parameters similar to thosethat would be used in the simple intermittent mode describedhereinabove. Correspondingly, during exercise, stimulation is applied soas to produce a heart rate of MAX(60 BPM, 70% of 150 BPM)=105 BPM.

In an embodiment of the present invention, a heart rate regulationalgorithm used by control unit 20 has as an input a time derivative ofthe sensed heart rate. The algorithm typically directs the control unitto respond slowly to increases in heart rate and quickly to decreases inheart rate.

In an embodiment of the present invention, the heart rate regulationalgorithm utilizes sensed physiological parameters for feedback. Forsome applications, the feedback is updated periodically by inputting thecurrent heart rate. For some applications, such updating occurs atequally-spaced intervals. Alternatively, the feedback is updated byinputting the current heart rate upon each detection of a feature of theECG, such as an R-wave. In order to convert non-fixed R-R intervals intoa form similar to canonical fixed intervals, the algorithm adds thesquare of each R-R interval, thus taking into account the non-uniformityof the update interval, e.g., in order to properly analyze feedbackstability using standard tools and methods developed for canonicalfeedback.

In an embodiment of the present invention, control unit 20 implements adetection blanking period, during which the control unit does not detectheart beats. In some instances, such non-detection may reduce falsedetections of heart beats. One or both of the following techniques aretypically implemented:

-   -   Absolute blanking. An expected maximal heart rate is used to        determine a minimum interval between expected heart beats.        During this interval, the control unit does not detect heart        beats, thereby generally reducing false detections. For example,        the expected maximal heart rate may be 200 BPM, resulting in a        minimal detection interval of 300 milliseconds. After detection        of a beat, the control unit disregards any signals indicative of        a beat during the next 300 milliseconds.    -   Stimulation blanking. During application of a stimulation burst,        and for an interval thereafter, the control unit does not detect        heart beats, thereby generally reducing false detections of        stimulation artifacts as beats. For example, assume stimulation        is applied with the following parameters: a PPT of 5 pulses, a        pulse width of 1 ms, and a pulse repetition interval of 5 ms.        The control unit disregards any signals indicative of a beat        during the entire 25 ms duration of the burst and for an        additional interval thereafter, e.g., 50 ms, resulting in a        total blanking period of 75 ms beginning with the start of the        burst.

In an embodiment of the present invention, the heart rate regulationalgorithm is implemented using only integer arithmetic. For example,division is implemented as integer division by a power of two, andmultiplication is always of two 8-bit numbers. For some applications,time is measured in units of 1/128 of a second.

In an embodiment of the present invention, control unit 20 implements anintegral feedback controller, which can most generally be described by:K=K _(I) *∫edtin which K represents the strength of the feedback, K_(I) is acoefficient, and ∫e dt represents the cumulative error. It is to beunderstood that such an integral feedback controller can be implementedin hardware, or in software running in control unit 20.

In an embodiment of such an integral controller, heart rate is typicallyexpressed as an R-R interval (the inverse of heart rate). Parameters ofthe integral controller typically include TargetRR (the target R-Rinterval) and TimeCoeff (which determines the overall feedback reactiontime).

Typically, following the detection of each R-wave, the previous R-Rinterval is calculated and assigned to a variable (LastRR). e (i.e., thedifference between the target R-R interval and the last measured R-Rinterval) is then calculated as:e=TargetRR−LastRRe is typically limited by control unit 20 to a certain range, such asbetween −0.25 and +0.25 seconds, by reducing values outside the range tothe endpoint values of the range. Similarly, LastRR is typicallylimited, such as to 255/128 seconds. The error is then calculated bymultiplying LastRR by e:Error=e*LastRR

A cumulative error (representing the integral in the above generalizedequation) is then calculated by dividing the error by TimeCoeff andadding the result to the cumulative error, as follows:Integral=Integral+Error/2^(TimeCoeff)The integral is limited to positive values less than, e.g., 36,863. Thenumber of pulses applied in the next series of pulses (pulses pertrigger, or PPT) is equal to the integral/4096.

The following table illustrates example calculations using a heart rateregulation algorithm that implements an integral controller, inaccordance with an embodiment of the present invention. In this example,the parameter TargetRR (the target heart rate) is set to 1 second (128/128 seconds), and the parameter TimeCoeff is set to 0. The initialvalue of Integral is 0. As can be seen in the table, the number ofpulses per trigger (PPT) increases from 0 during the first heart beat,to 2 during the fourth heart beat of the

Heart Beat Number 1 2 3 4 Heart rate (BPM) 100 98 96 102 R—R interval(ms) 600 610 620 590 R—R ( 1/128 sec) 76 78 79 75 e ( 1/128 sec) 52 5049 53 Limited e 32 32 32 32 Error 2432 2496 2528 2400 Integral 2432 49287456 9856 PPT 0 1 1 2

In an embodiment of the present invention, the heart rate regulationalgorithm corrects for missed heart beats (either of physiologicalorigin or because of a failure to detect a beat). Typically, to performthis correction, any R-R interval which is about twice as long as theimmediately preceding R-R interval is interpreted as two R-R intervals,each having a length equal to half the measured interval. For example,the R-R interval sequence (measured in seconds) 1, 1, 1, 2.2 isinterpreted by the algorithm as the sequence 1, 1, 1, 1.1, 1.1.Alternatively or additionally, the algorithm corrects for prematurebeats, typically by adjusting the timing of beats that do not occurapproximately halfway between the preceding and following beats. Forexample, the R-R interval sequence (measured in seconds) 1, 1, 0.5, 1.5is interpreted as 1, 1, 1, 1, using the assumption that the third beatwas premature.

In an embodiment of the present invention, control unit 20 is configuredto operate in one of the following modes:

-   -   vagal stimulation is not applied when the heart rate of the        subject is lower than the low end of the normal range of a heart        rate of the subject and/or of a typical human subject;    -   vagal stimulation is not applied when the heart rate of the        subject is lower than a threshold value equal to the current low        end of the range of the heart rate of the subject, i.e., the        threshold value is variable over time as the low end generally        decreases as a result of chronic vagal stimulation treatment;    -   vagal stimulation is applied only when the heart rate of the        subject is within the normal of range of a heart rate of the        subject and/or of a typical human subjects;    -   vagal stimulation is applied only when the heart rate of the        subject is greater than a programmable threshold value, such as        a rate higher than a normal rate of the subject and/or a normal        rate of a typical human subject. This mode generally removes        peaks in heart rate; or    -   vagal stimulation is applied using fixed programmable        parameters, i.e., not in response to any feedback, target heart        rate, or target heart rate range. These parameters may be        externally updated from time to time, for example by a        physician.

In an embodiment of the present invention, the amplitude of the appliedstimulation current is calibrated by fixing a number of pulses in theseries of pulses (per cardiac cycle), and then increasing the appliedcurrent until a desired pre-determined heart rate reduction is achieved.Alternatively, the current is calibrated by fixing the number of pulsesper series of pulses, and then increasing the current to achieve asubstantial reduction in heart rate, e.g., 40%.

In embodiments of the present invention in which vagal stimulationsystem 18 comprises implanted device 25 for monitoring and correctingthe heart rate, control unit 20 typically uses measured parametersreceived from device 25 as additional inputs for determining the leveland/or type of stimulation to apply. Control unit 20 typicallycoordinates its behavior with the behavior of device 25. Control unit 20and device 25 typically share sensors 26 in order to avoid redundancy inthe combined system.

Optionally, vagal stimulation system 18 comprises a patient override,such as a switch that can be activated by the patient using an externalmagnet. The override typically can be used by the patient to activatevagal stimulation, for example in the event of arrhythmia apparentlyundetected by the system, or to deactivate vagal stimulation, forexample in the event of apparently undetected physical exertion.

FIG. 5 is a simplified illustration of an ECG recording 70 and exampletimelines 72 and 76 showing the timing of the application of a burst ofstimulation pulses 74, in accordance with an embodiment of the presentinvention. Stimulation is typically applied to vagus nerve 36 in aclosed-loop system in order to achieve and maintain the desired targetheart rate, determined as described above. Precise graded slowing of theheart beat is typically achieved by varying the number of nerve fibersstimulated, in a smaller-to-larger diameter order, and/or the intensityof vagus nerve stimulation, such as by changing the stimulationamplitude, pulse width, PPT, and/or delay. Stimulation with blocking, asdescribed herein, is typically applied during each cardiac cycle inburst of pulses 74, typically containing between about 1 and about 20pulses, each of about 1-3 milliseconds duration, over a period of about1-200 milliseconds. Advantageously, such short pulse durations generallydo not substantially block or interfere with the natural efferent orafferent action potentials traveling along the vagus nerve.Additionally, the number of pulses and/or their duration is sometimesvaried in order to facilitate achievement of precise graded slowing ofthe heart beat.

In an embodiment of the present invention (e.g., when the heart rateregulation algorithm described hereinabove is not implemented), to applythe closed-loop system, the target heart rate is expressed as aventricular R-R interval (shown as the interval between R₁ and R₂ inFIG. 5). The actual R-R interval is measured in real time and comparedwith the target R-R interval. The difference between the two intervalsis defined as a control error. Control unit 20 calculates the change instimulation necessary to move the actual R-R towards the target R-R, anddrives electrode device 40 to apply the new calculated stimulation.Intermittently, e.g., every 1, 10, or 100 beats, measured R-R intervalsor average R-R intervals are evaluated, and stimulation of the vagusnerve is modified accordingly.

In an embodiment, vagal stimulation system 18 is further configured toapply stimulation responsive to pre-set time parameters, such asintermittently, constantly, or based on the time of day.

Alternatively or additionally, one or more of the techniques ofsmaller-to-larger diameter fiber recruitment, selective fiber populationstimulation and blocking, and varying the intensity of vagus nervestimulation by changing the stimulation amplitude, pulse width, PPT,and/or delay, are applied in conjunction with methods and apparatusdescribed in one or more of the patents, patent applications, articlesand books cited herein.

In an embodiment of the present invention, control unit 20 is configuredto stimulate vagus nerve 36 so as to suppress the adrenergic system, inorder to treat a subject suffering from a heart condition. For example,such vagal stimulation may be applied for treating a subject sufferingfrom heart failure. In heart failure, hyper-activation of the adrenergicsystem damages the heart. This damage causes further activation of theadrenergic system, resulting in a vicious cycle. High adrenergic tone isharmful because it often results in excessive release of angiotensin andepinephrine, which increase vascular resistance (blood pressure), reduceheart rest time (accelerated heart rate), and cause direct toxic damageto myocardial muscles through oxygen free radicals and DNA damage.Artificial stimulation of the vagus nerve causes a down regulation ofthe adrenergic system, with reduced release of catecholamines. Thenatural effects of vagal stimulation, applied using the techniquesdescribed herein, typically reduces the release of catecholamines in theheart, thereby lowering the adrenergic tone at its source.

In an embodiment of the present invention, control unit 20 is configuredto stimulate vagus nerve 36 so as to modulate atrial and ventricularcontractility, in order to treat a subject suffering from a heartcondition. Vagal stimulation generally reduces both atrial andventricular contractility (see, for example, the above-cited article byLevy M N et al., entitled “Parasympathetic Control of the Heart”). Vagalstimulation, using the techniques described herein, typically (a)reduces the contractility of the atria, thereby reducing the pressure inthe venous system, and (b) reduces the ventricular contractile force ofthe atria, which may reduce oxygen consumption, such as in cases ofischemia. For some applications, vagal stimulation, as described herein,is applied in order to reduce the contractile force of the ventricles incases of hypertrophic cardiopathy. The vagal stimulation is typicallyapplied with a current of at least about 4 mA.

In an embodiment of the present invention, control unit 20 is configuredto stimulate vagus nerve 36 so as to improve coronary blood flow, inorder to treat a subject suffering from a heart condition. Improvingcoronary blood flow by administering acetylcholine is a well knowntechnique. For example, during Percutaneous Transluminal CoronaryAngioplasty (PTCA), when maximal coronary dilation is needed, directinfusion of acetylcholine is often used to dilate the coronary arteries(see, for example, the above-cited article by Feliciano L et al.). Forsome applications, the vagal stimulation techniques described herein areused to improve coronary blood flow in subjects suffering frommyocardial ischemia, ischemic heart disease, heart failure, and/orvariant angina (spastic coronary arteries). It is hypothesized that suchvagal stimulation simulates the effect of acetylcholine administration.

In an embodiment of the present invention, control unit 20 is configuredto drive electrode device 40 to stimulate vagus nerve 36 so as to modifyheart rate variability of the subject. For some applications, controlunit 20 is configured to apply the stimulation having a duty cycle,which typically produces heart rate variability at the correspondingfrequency. For example, such duty cycles may be in the range of once perevery several heartbeats. For other applications, control unit 20 isconfigured to apply generally continuous stimulation (e.g., in a mannerthat produces a prolonged reduced level of heart rate variability).

For some applications, control unit 20 synchronizes the stimulation withthe cardiac cycle of the subject, while for other applications, thecontrol unit does not synchronize the stimulation with the cardiaccycle. For example, the stimulation may be applied in a series of pulsesthat are not synchronized with the cardiac cycle of the subject.Alternatively, the stimulation may be applied in a series of pulses thatare synchronized with the cardiac cycle of the subject, such asdescribed hereinabove with reference to FIG. 5.

For some applications, control unit 20 is configured to applystimulation with parameters selected to reduce heart rate variability,while for other applications parameters are selected that increasevariability. For example, when the stimulation is applied as a series ofpulses, values of parameters that reduce heart variability may includeone or more of the following:

-   -   Timing of the stimulation within the cardiac cycle: a delay of        between about 50 ms and about 150 ms from the R-wave, or between        about 100 and about 500 ms from the P-wave.    -   Pulse duration (width) of between about 0.5 and about 1.5 ms.    -   Pulse repetition interval (the time from the initiation of a        pulse to the initiation of the following pulse) of between about        2 and about 8 ms.    -   Pulses per trigger (PPT), e.g., pulses per cardiac cycle, of        between about 0 and about 8.    -   Amplitude of between about 5 and about 10 milliamps.

For some applications, the parameters of the stimulation are selected toboth reduce the heart rate of the subject and heart rate variability ofthe subject. For other applications, the parameters are selected toreduce heart rate variability while substantially not reducing theaverage heart rate of the subject. In this context, a non-substantialheart rate reduction may be less than about 10%. For some applications,to achieve such a reduction in variability without a reduction inaverage rate, stimulation is applied using the feedback techniquesdescribed hereinabove, with a target heart rate greater than the normalaverage heart rate of the subject. Such stimulation typically does notsubstantially change the average heart rate, yet reduces heart ratevariability (however, the instantaneous (but not average) heart rate maysometimes be reduced).

For some applications, in order to additionally reduce the heart rate,stimulation is applied using a target heart rate lower than the normalaverage heart rate of the subject. The magnitude of the change inaverage heart rate as well as the percentage of time during whichreduced heart rate variability occurs in these applications arecontrolled by varying the difference between the target heart rate andthe normal average heart rate.

For some applications, control unit 20 is configured to applystimulation only when the subject is awake. Reducing heart variabilitywhen the subject is awake offsets natural increases in heart ratevariability during this phase of the circadian cycle. Alternatively oradditionally, control unit 20 is configured to apply or apply greaterstimulation at times of exertion by the subject, in order to offset theincrease in heart rate variability typically caused by exertion. Forexample, control unit 20 may determine that the subject is experiencingexertion responsive to an increase in heart rate, or responsive to asignal generated by an accelerometer. Alternatively, the control unituses other techniques known in the art for detecting exertion.

In an embodiment of the present invention, control unit 20 is configuredto drive electrode device 40 to stimulate vagus nerve 36 so as to modifyheart rate variability in order to treat a condition of the subject. Forsome applications, the control unit is configured to additionally modifyheart rate to treat the condition, while for other applications, thecontrol unit is configured to modify heart rate variability whilesubstantially not modifying average heart rate.

Therapeutic effects of reduction in heart rate variability include, butare not limited to:

-   -   Narrowing of the heart rate range, thereby eliminating very slow        heart rates and very fast heart rates, both of which are        inefficient for a subject suffering from heart failure. For this        therapeutic application, control unit 20 is typically configured        to reduce low-frequency heart rate variability, and to adjust        the level of stimulation applied based on the circadian and        activity cycles of the subject.    -   Stabilizing the heart rate, thereby reducing the occurrence of        arrhythmia. For this therapeutic application, control unit 20 is        typically configured to reduce heart rate variability at all        frequencies.    -   Maximizing the mechanical efficiency of the heart by maintaining        relatively constant ventricular filling times and pressures. For        example, this therapeutic effect may be beneficial for subjects        suffering from atrial fibrillation, in which fluctuations in        heart filling times and pressure reduce cardiac efficiency.    -   Eliminating the normal cardiac response to changes in the        breathing cycle (i.e., respiratory sinus arrhythmia). Although        generally beneficial in young and efficient hearts, respiratory        sinus arrhythmia may be harmful to subjects suffering from heart        failure, because respiratory sinus arrhythmia causes unwanted        accelerations and decelerations in the heart rate. For this        therapeutic application, control unit 20 is typically configured        to reduce heart rate variability at high frequencies.

Reference is now made to FIG. 6, which is a graph showing in vivoexperimental results, measured in accordance with an embodiment of thepresent invention. A dog was anesthetized, and cuff electrodes, similarto those described hereinabove with reference to FIG. 2B, were implantedin the right cervical vagus nerve. After a recovery period of two weeks,experimental vagal stimulation was applied to the dog while the dog wasawake and allowed to move freely within its cage.

A control unit, similar to control unit 20, was programmed to applyvagal stimulation in a series of pulses, having the followingparameters:

-   -   Stimulation synchronized with the intracardiac R-wave signal,        with a delay from the R-wave of 60 ms;    -   Stimulation amplitude of 8 mA;    -   Stimulation pulse duration of 1 ms; and    -   Time between pulses within a burst of 5 ms.        The control unit implemented an integral feedback controller,        similar to the integral feedback controller described        hereinabove, in order to vary the number of pulses within a        burst. The integral feedback controller used a target heart rate        of 80 beats per minute. After 2 minutes of stimulation, the        number of pulses within each burst was typically between about 1        and about 8.

During a first period and a third period from 0 to 18 minutes and 54 to74 minutes, respectively, the control unit applied stimulation to thevagus nerve. Heart rate variability was substantially reduced, while anaverage heart rate of 80 beats per minute was maintained. (Baselineheart rate, without stimulation, was approximately 95 beats per minute.)During a second period and a fourth period from 18 to 54 minutes and 74to 90 minutes, respectively, stimulation was discontinued, and, as aresult, heart rate variability increased substantially, returning tonormal values. Average heart rate during these non-stimulation periodsincreased to approximately 95 beats per minute (approximately baselinevalue). Thus, these experimental results demonstrate that theapplication of vagal stimulation using some of the techniques describedherein results in a substantial reduction in heart rate variability.

Although embodiments of the present invention are described herein, insome cases, with respect to treating specific heart conditions, it is tobe understood that the scope of the present invention generally includesutilizing the techniques described herein to controllably stimulate thevagus nerve to facilitate treatments of, for example, heart failure,atrial fibrillation, and ischemic heart diseases. In particular, thetechniques described herein may be performed in combination with othertechniques, which are well known in the art or which are described inthe references cited herein, that stimulate the vagus nerve in order toachieve a desired therapeutic end.

For some applications, techniques described herein are used to applycontrolled stimulation to one or more of the following: the lacrimalnerve, the salivary nerve, the vagus nerve, the pelvic splanchnic nerve,or one or more sympathetic or parasympathetic autonomic nerves. Suchcontrolled stimulation may be used, for example, to regulate or treat acondition of the lung, heart, stomach, pancreas, small intestine, liver,spleen, kidney, bladder, rectum, large intestine, reproductive organs,or adrenal gland.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description.

1. Apparatus comprising: an electrode device, configured to be coupledto a site of a subject selected from the group consisting of: a vagusnerve, and an epicardial fat pad; a cardiac monitor, configured todetect a cardiac signal; and a control unit, configured to: drive theelectrode device to apply a current to the site in respective pulsebursts in each of a plurality of cardiac cycles of the subject, andconfigure the current to reduce heart rate variability of the subjectbelow a baseline heart rate variability of the subject which correspondsto the subject's heart rate variability when the current is not applied,by initiating the applying of each burst after a delay of 30 to 200milliseconds following an R-wave of the cardiac signal.
 2. The apparatusaccording to claim 1, wherein the control unit is configured toconfigure the current to substantially not reduce a heart rate of thesubject.
 3. The apparatus according to claim 1, wherein the control unitis configured to configure the current to reduce the heart ratevariability by at least 5% below the baseline heart rate variability. 4.The apparatus according to claim 3, wherein the control unit isconfigured to configure the current to reduce the heart rate variabilityby at least 5% below the baseline heart rate variability during a timeperiod in which a heart rate of the subject is not reduced responsive tothe current by more than 10% below a baseline thereof.
 5. The apparatusaccording to claim 1, wherein the control unit is configured to drivethe electrode device during exertion by the subject.
 6. The apparatusaccording to claim 1, wherein the control unit is configured to withholddriving the electrode device when the subject is not experiencingexertion.
 7. The apparatus according to claim 1, wherein the controlunit is configured to configure the current to reduce a heart ratevariability of the subject having a characteristic frequency betweenabout 0.15 and about 0.4 Hz.
 8. The apparatus according to claim 1,wherein the control unit is configured to configure the current toreduce a heart rate variability of the subject having a characteristicfrequency between about 0.04 and about 0.15 Hz.
 9. The apparatusaccording to claim 1, wherein the control unit is configured to drivethe electrode device to apply the current in intermittent ones of aplurality of cardiac cycles of the subject.
 10. The apparatus accordingto claim 1, wherein the control unit is configured to drive theelectrode device responsive to a circadian rhythm of the subject. 11.The apparatus according to claim 10, wherein the control unit isconfigured to drive the electrode device when the subject is awake. 12.The apparatus according to claim 10, wherein the control unit isconfigured to withhold driving the electrode device when the subject issleeping.
 13. The apparatus according to claim 1, wherein the controlunit is configured to configure the current to reduce the heart ratevariability by at least 10%.
 14. The apparatus according to claim 13,wherein the control unit is configured to configure the current toreduce the heart rate variability by at least 50%.
 15. The apparatusaccording to claim 1, wherein the control unit is configured toconfigure the current to reduce a standard deviation of a heart rate ofthe subject within a time window.
 16. The apparatus according to claim15, wherein the control unit is configured to configure the current toreduce a standard deviation of the heart rate of the subject within atime window longer than 10 seconds.
 17. The apparatus according to claim16, wherein the control unit is configured to configure the current toreduce by at least about 10% the standard deviation of the heart ratewithin the time window longer than 10 seconds.
 18. The apparatusaccording to claim 17, wherein the control unit is configured toconfigure the current to reduce by at least about 50% the standarddeviation of the heart rate within the time window longer than 10seconds.
 19. The apparatus according to claim 1, wherein the controlunit is configured to configure each pulse of each of the bursts to havea pulse duration of between about 0.1 and about 4 milliseconds.
 20. Theapparatus according to claim 19, wherein the control unit is configuredto configure each pulse of each of the bursts to have a pulse durationof between about 0.5 and about 2 milliseconds.
 21. The apparatusaccording to claim 1, wherein the control unit is configured toconfigure each of the bursts to have a pulse repetition interval ofbetween about 2 and about 10 milliseconds.
 22. The apparatus accordingto claim 21, wherein the control unit is configured to configure each ofthe bursts to have a pulse repetition interval of between about 2 andabout 6 milliseconds.
 23. The apparatus according to claim 1, whereinthe control unit is configured to initiate the applying of each burstafter a delay of about 50 to about 150 milliseconds following the R-waveof the cardiac signal.
 24. The apparatus according to claim 1, whereinthe control unit is configured to configure at least one of the burststo have between about 0 and about 20 pulses.
 25. The apparatus accordingto claim 24, wherein the control unit is configured to configure thebursts to have between about 1 and about 8 pulses during steady stateoperation.
 26. The apparatus according to claim 1, wherein the controlunit is configured to configure the current to reduce a heart rate ofthe subject.
 27. The apparatus according to claim 26, wherein thecardiac monitor is configured to detect the heart rate of the subject,and to generate a heart rate signal responsive thereto, wherein thecontrol unit is configured to configure the current to reduce the heartrate of the subject toward a target heart rate, responsively to theheart rate signal.
 28. The apparatus according to claim 27, wherein thetarget heart rate includes a target normal heart rate within a range ofnormal heart rates of the subject, and wherein the control unit isconfigured to configure the current to reduce the heart rate of thesubject toward the target normal heart rate.
 29. The apparatus accordingto claim 27, wherein the control unit comprises an integral feedbackcontroller that has inputs comprising the detected heart rate and thetarget heart rate, and wherein the control unit is configured toconfigure the current responsively to an output of the integral feedbackcontroller.
 30. The apparatus according to claim 27, wherein the targetheart rate is lower than a normal average heart rate of the subject, andwherein the control unit is configured to configure the current toreduce the heart rate of the subject toward the target heart rate. 31.The apparatus according to claim 1, wherein the control unit isconfigured to configure the current to treat a condition of the subjectby reducing the heart rate variability.
 32. The apparatus according toclaim 31, wherein the condition includes heart failure of the subject,and wherein the control unit is configured to configure the current toreduce the heart rate variability by at least about 10% so as to treatthe heart failure.
 33. The apparatus according to claim 31, wherein thecondition includes an occurrence of arrhythmia of the subject, andwherein the control unit is configured to configure the current toreduce the heart rate variability by at least about 10% so as to treatthe occurrence of arrhythmia.
 34. The apparatus according to claim 33,wherein the condition includes atrial fibrillation of the subject, andwherein the control unit is configured to configure the current toreduce the heart rate variability so as to treat the atrialfibrillation.
 35. The apparatus according to claim 1, wherein thecontrol unit is configured to drive the electrode device to apply thecurrent with an amplitude of between about 2 and about 10 milliamps. 36.The apparatus according to claim 1, wherein the control unit isconfigured to configure the current to cause a prolonged reduced levelof the heart rate variability.
 37. The method according to claim 1,wherein applying the current comprises configuring the current to reducethe heart rate variability by at least 5% below the baseline heart ratevariability.
 38. The method according to claim 37, wherein configuringthe current comprises configuring the current to reduce the heart ratevariability by at least 5% below the baseline heart rate variabilityduring a time period in which a heart rate of the subject is not reducedresponsive to the current by more than 10% below a baseline thereof. 39.A method comprising: identifying a subject as being appropriate forreduction of heart rate variability of the subject below a baselineheart rate variability of the subject which corresponds to the subject'sheart rate variability when parasympathetic stimulation is not applied;applying a current to a site of the subject selected from the groupconsisting of: a vagus nerve, and an epicardial fat pad; and in responseto the identifying, treating a condition of the subject by reducing theheart rate variability below the baseline heart rate variability, byconfiguring the current.
 40. The method according to claim 39, whereinapplying the current comprises configuring the current to substantiallynot reduce a heart rate of the subject.
 41. The method according toclaim 39, wherein applying the current comprises detecting exertion bythe subject and applying the current during the exertion.
 42. The methodaccording to claim 39, wherein applying the current comprises: detectingwhether the subject is experiencing exertion; and withholding applyingthe current when the subject is not experiencing exertion.
 43. Themethod according to claim 39, wherein applying the current comprisesconfiguring the current to reduce a heart rate variability of thesubject having a characteristic frequency between about 0.15 and about0.4 Hz.
 44. The method according to claim 39, wherein applying thecurrent comprises configuring the current to reduce a heart ratevariability of the subject having a characteristic frequency betweenabout 0.04 and about 0.15 Hz.
 45. The method according to claim 39,wherein applying the current comprises applying the current inintermittent ones of a plurality of cardiac cycles of the subject. 46.The method according to claim 39, wherein applying the current comprisesapplying the current responsive to a circadian rhythm of the subject.47. The method according to claim 46, wherein applying the currentcomprises applying the current when the subject is awake.
 48. The methodaccording to claim 46, wherein applying the current compriseswithholding applying the current when the subject is sleeping.
 49. Themethod according to claim 39, wherein applying the current comprisesconfiguring the current to reduce the heart rate variability by at least10%.
 50. The method according to claim 49, wherein applying the currentcomprises configuring the current to reduce the heart rate variabilityby at least 50%.
 51. The method according to claim 39, wherein applyingthe current comprises configuring the current to reduce a standarddeviation of a heart rate of the subject within a time window.
 52. Themethod according to claim 51, wherein applying the current comprisesconfiguring the current to reduce a standard deviation of the heart rateof the subject within a time window longer than 10 seconds.
 53. Themethod according to claim 52, wherein applying the current comprisesconfiguring the current to reduce by at least about 10% the standarddeviation of the heart rate within the time window longer than 10seconds.
 54. The method according to claim 53, wherein applying thecurrent comprises configuring the current to reduce by at least about50% the standard deviation of the heart rate within the time windowlonger than 10 seconds.
 55. The method according to claim 39, whereinapplying the current comprises configuring each pulse of each of thebursts to have a pulse duration of between about 0.1 and about 4milliseconds.
 56. The method according to claim 55, wherein applying thecurrent comprises configuring each pulse of each of the bursts to have apulse duration of between about 0.5 and about 2 milliseconds.
 57. Themethod according to claim 39, wherein applying the current comprisesconfiguring each of the bursts to have a pulse repetition interval ofbetween about 2 and about 10 milliseconds.
 58. The method according toclaim 57, wherein applying the current comprises configuring each of thebursts to have a pulse repetition interval of between about 2 and about6 milliseconds.
 59. The method according to claim 39, wherein applyingthe current comprises initiating the applying of each burst after adelay of about 50 to about 150 milliseconds following the R-wave of thecardiac signal.
 60. The method according to claim 39, wherein applyingthe current comprises configuring at least one of the bursts to havebetween about 0 and about 20 pulses.
 61. The method according to claim60, wherein applying the current comprises configuring the bursts tohave between about 1 and about 8 pulses during steady state operation.62. The method according to claim 39, wherein applying the currentcomprises configuring the current to reduce a heart rate of the subject.63. The method according to claim 62, wherein applying the currentcomprises detecting the heart rate of the subject, and configuring thecurrent to reduce the heart rate of the subject toward a target heartrate, responsively to the heart rate.
 64. The method according to claim63, wherein configuring the current comprises configuring the current toreduce the heart rate toward the target heart rate responsively to anoutput of an integral feedback controller whose inputs comprise thedetected heart rate and the target heart rate.
 65. The method accordingto claim 63, wherein the target heart rate is lower than a normalaverage heart rate of the subject, and wherein applying the currentcomprises configuring the current to reduce the heart rate of thesubject toward the target heart rate.
 66. The method according to claim63, wherein the target heart rate includes a target normal heart ratewithin a range of normal heart rates of the subject, and whereinapplying the current comprises configuring the current to reduce theheart rate of the subject toward the target normal heart rate.
 67. Themethod according to claim 39, wherein the condition includes heartfailure of the subject, and wherein treating the condition comprisesconfiguring the current to reduce the heart rate variability by at leastabout 10% so as to treat the heart failure.
 68. The method according toclaim 39, wherein the condition includes an occurrence of arrhythmia ofthe subject, and wherein treating the condition comprises configuringthe current to reduce the heart rate variability by at least about 10%so as to treat the occurrence of arrhythmia.
 69. The method according toclaim 68, wherein the condition includes atrial fibrillation of thesubject, and wherein treating the condition comprises configuring thecurrent to reduce the heart rate variability so as to treat the atrialfibrillation.
 70. The method according to claim 39, wherein applying thecurrent comprises applying the current with an amplitude of betweenabout 2 and about 10 milliamps.
 71. The method according to claim 39,wherein configuring the current comprises configuring the current tocause a prolonged reduced level of the heart rate variability.
 72. Amethod comprising: detecting a cardiac signal of the subject; applying acurrent to a site of a subject in respective pulse bursts in each of aplurality of cardiac cycles of the subject, the site selected from thegroup consisting of: a vagus nerve, and an epicardial fat pad; andconfiguring the current to reduce heart rate variability of the subjectbelow a baseline heart rate variability of the subject which correspondsto the subject's heart rate variability when the current is not applied,by initiating the applying of each burst after a delay of 30 to 200milliseconds following an R-wave of the cardiac signal.